RU2269529C2 - Derivatives of quinoline xanthine and 8-isoquinoline xanthine as inhibitors of phosphodiesterase pde-5 - Google Patents

Abstract

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention proposes compound of the formula (1)

in free form or as a salt wherein R¹, R², R³, R⁴ and R⁵ have values given in the invention claim. The claimed compounds are selective inhibitors of enzyme PDE-5 and show the high selectivity in inhibition of activity of 3',5'-cycloguanosine monophosphate phosphodiesterase being activity of PDE-5 first of all.

EFFECT: valuable biochemical properties of derivatives.

6 cl, 3 tbl, 87 ex

Description

The invention relates to organic compounds, their preparation and use as pharmaceuticals.

First of all, the invention relates to compounds of the formula

in free form or in salt form, where

R ¹ is hydrogen or alkyl optionally substituted with a hydroxy, alkoxy or alkylthio group,

R ² is hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, in which the aryl ring is optionally fused with a 5-membered heterocycle or optionally substituted with one or more substituents selected from alkylamino, dialkylamino, acylamino, halogen, hydroxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino or dialkylaminosulfonylamino,

R ³ is hydrogen or alkyl optionally substituted with a hydroxy, alkoxy or alkylthio group,

R ⁴ means hydrogen or alkyl,

R ⁵ means a quinolinyl, isoquinolinyl or oxo-dihydroisoquinolinyl group, optionally fused to a 5-membered heterocycle and optionally substituted with one or more substituents selected from the group halo, cyano, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkoxy, alkylthio, alkyl alkynyl, carboxyl, acyl, a group of the formula —N (R ⁶ ) R ⁷ , aryl optionally substituted with one or more substituents selected from the range of halogen or alkoxy, or heteroaryl containing 5 or 6 atoms in a ring and bonded via carbon atom in the cycle with the specified carbon atom, and

R ⁶ and R ⁷ each independently of one another is hydrogen or alkyl optionally substituted with a hydroxy or alkoxy group, or one of R ⁶ and R ⁷ is hydrogen and the other is acyl, or R ⁶ and R ⁷ together with a nitrogen atom, to which they are attached means a 5- or 6-membered heterocyclyl group.

The term “alkyl”, as used herein, means straight or branched chain alkyl, for example C ₁ -C ₁₀ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, straight or branched octyl, straight or branched nonyl, or straight or branched decyl. Preferably, alkyl is C ₁ -C ₈ alkyl.

The term “alkoxy” as used in the application text means straight or branched chain alkoxy, for example C ₁ -C ₁₀ alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, straight or branched octyloxy, straight or branched nonyloxy, or straight or branched decyloxy. Preferred alkoxy is C ₁ -C ₄ alkoxy.

The term “alkylthio” as used throughout the application means C ₁ -C ₁₀ alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio octylthio, nonylthio or decylthio. Preferred alkylthio is C ₁ -C ₄ alkylthio.

The term “alkenyl” as used in the application text means straight or branched chain alkenyl, for example C ₂ -C ₁₀ alkenyl, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl or straight or branched pentenyl, hexenyl , heptenyl, octenyl, nonenyl or decenyl. Preferred alkenyl means C ₁ -C ₄ alkenyl.

The term “cycloalkylalkyl” as used herein means alkyl, for example C ₁ -C ₁₀ alkyl, such as one of the aforementioned C ₁ -C ₁₀ alkyl groups, substituted with a C ₃ -C ₈ cycloalkyl group, such as cyclopropyl, methylcyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl or cyclooctyl. Preferred cycloalkylalkyl means C ₃ -C ₆ cycloalkyl (C ₁ -C ₄ ) alkyl.

The term “heterocyclylalkyl”, as used herein, means alkyl, for example C ₁ -C ₁₀ alkyl, such as one of the aforementioned C ₁ -C ₁₀ alkyl groups, substituted with a 5- or 6-membered heterocyclyl group containing one or two rings heteroatoms selected from the series nitrogen, oxygen and sulfur, such as pyrrolyl, pyrrolidinyl, furyl, thienyl, pyridyl, piperidyl, imidazolyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, oxazolyl or furazanyl. Preferred heterocyclylalkyl means C ₁ -C ₄ alkyl substituted with a 5- or 6-membered heterocyclyl group containing one or two nitrogen or oxygen atoms or one nitrogen atom and one oxygen atom in the ring.

The term “aralkyl” as used in the application text means C ₆ -C ₁₀ aryl (C ₁ -C ₁₀ ) alkyl, for example, such as one of the aforementioned C ₁ -C ₁₀ alkyl groups, especially one of C ₁ -C ₄ alkyl groups substituted with phenyl, tolyl, xylyl or naphthyl. Preferred aralkyl means phenyl (C ₁ -C ₄ ) alkyl, especially benzyl or 2-phenylethyl.

The term “acyl” as used throughout the application means alkyl carbonyl, for example C ₁ -C ₁₀ alkylcarbonyl, where C ₁ -C ₁₀ alkyl means one of the aforementioned C ₁ -C ₁₀ alkyl groups, optionally substituted with one or more halogen atoms; cycloalkylcarbonyl, for example C ₃ -C ₈ cycloalkylcarbonyl, where C ₃ -C ₈ cycloalkyl may mean, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6-membered heterocyclylcarbonyl containing one or two atoms in a cycle selected from the group of nitrogen, oxygen and sulfur, such as furylcarbonyl or pyridylcarbonyl; arylcarbonyl, for example C ₆ -C ₁₀ arylcarbonyl, such as benzoyl; or aralkylcarbonyl, for example C ₆ -C ₁₀ aryl (C ₁ -C ₄ ) alkylcarbonyl, such as benzylcarbonyl or phenylethylcarbonyl. Preferred acyl means C ₁ -C ₄ alkylcarbonyl.

The term “alkynyl”, as used herein, means straight or branched alkynyl, for example C ₂ -C ₆ alkynyl, such as ethynyl, propargyl, 2-butynyl, pentynyl or hexynyl. Preferred alkynyl means C ₂ -C ₄ alkynyl.

The term “aryl” as used in the application text means a monovalent carbocyclic aromatic group, for example, C ₆ -C ₁₀ aryl, such as phenyl, phenyl substituted with one or more, for example, one, two or three, C ₁ -C ₄ alkyl groups, or naphthyl. Preferred aryl means phenyl.

The term “heteroaryl containing in a cycle of 5 or 6 atoms”, used in the text of the application, means a monovalent aromatic heterocyclic group containing in a cycle of 5 or 6 atoms, of which one, two or three atoms are selected from the series nitrogen, oxygen and sulfur, such such as pyrrolyl, furyl, thienyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dithiazolyl, trithiazolyl, furazanyl, pyrazinyl, pyrimidinyl or triazinyl.

The alkyl, acyl or alkoxy groups of the alkylamino, dialkylamino, acylamino, dialkylaminosulfonylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, hydroxyalkyl, alkylthioalkyl and alkoxyalkyl radicals are as defined above.

The term “halogen” as used in the application text means fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.

A 5-membered heterocycle that is optionally fused to R ⁵ , such as quinolinyl, isoquinolinyl or oxo-dihydroisoquinolinyl, can mean, for example, a 5-membered heterocycle containing one or two heteroatoms in the ring, said atoms being selected from the range of oxygen, nitrogen and sulfur. Examples of such heterocycles include pyrrole, pyrroline, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, diazole, diazole, diazole, diazole, diazole. A preferred 5 membered heterocycle means a saturated ring containing two heteroatoms, preferably two oxygen atoms or two nitrogen atoms, especially two oxygen atoms.

R ⁵ as a quinolinyl group may mean a 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8-quinolinyl group, preferably a 4-quinolinyl, 5-quinolinyl or 8-quinolinyl group . R ⁵ as an isoquinolinyl group may mean a 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 6-isoquinolinyl or 8-isoquinolinyl group, preferably a 1-isoquinolinyl or 4-isoquinolinyl group. In a most preferred embodiment of the invention, R ⁵ is a 4-isoquinolinyl group.

R ⁵ as a group substituted quinolinyl or isoquinolinyl is preferably substituted with one, two, three or four of the above substituents, especially one, two or three of these substituents. A preferred substituted 4-isoquinolinyl group is preferably substituted at position 1, and / or 6, and / or 7, and / or 8 of the isoquinolinyl ring system.

In more preferred embodiments, R ⁵ is a quinolinyl group of the formula

or an isoquinolinyl group of the formula

where R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently means hydrogen or a substituent selected from the range of halogen, cyano, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkoxy, alkylthio, alkenyl, alkoxycarbonyl, alkynyl, carboxyl, acyl, a group of the formula —N (R ⁶ ) R ⁷ , aryl optionally substituted with one or more substituents selected from the range of halogen or alkoxy, or heteroaryl containing 5 or 6 atoms in the ring, or R ¹¹ and R ¹² together with the carbon atoms to which they are attached, mean a 5-membered heterocyclic group containing in the cycle two atoms of oxygen or nitrogen, and R ⁶ and R ⁷ have the meanings indicated above.

R ⁵ in the form of a group of oxo dihydroisoquinolinyl preferably contains an oxo group in the ortho position to the nitrogen atom in the ring, preferably in position 1 of the isoquinoline ring system. This system is preferably connected to the rest of the molecule of formula I through a carbon atom in the ring located in the meta position to the nitrogen atom, i.e. in position 4 of the isoquinoline ring system. A more preferred group is oxodihydroisoquinoline of the formula

where R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are as defined above, and R ^a is hydrogen or C ₁ -C ₄ alkyl.

Of the compounds of formula I in free or salt form, preferred are those wherein

R ¹ is hydrogen or C ₁ -C ₄ alkyl optionally substituted with a hydroxy group, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylthio,

R ² means hydrogen, C ₁ -C ₈ alkyl, hydroxy (C ₁ -C ₈ ) alkyl, C ₁ -C ₄ alkylcarbonyloxy (C ₁ -C ₈ ) alkyl, C ₁ -C ₄ alkoxy (C ₁ -C ₈ ) alkyl, C ₁ -C ₄ alkylthio (C ₁ -C ₈ ) alkyl, C ₂ -C ₄ alkenyl, C ₃ -C ₈ cycloalkyl (C ₁ -C ₄ ) alkyl, heterocyclyl (C ₁ -C ₄ ) alkyl, where heterocyclyl group means a 5- or 6-membered heterocyclyl group containing in the cycle one or two heteroatoms selected from nitrogen and oxygen atoms, phenyl (C ₁ -C ₄ ) alkyl, where phenyl is optionally substituted with one or more substituents selected from series C C ₁ -C ₄ alkoxy, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄₎ alkylamino, C ₁ -C ₄ al ylcarbonylamino, halogen, C ₁ -C ₄ alkylsulfonylamino or di (C ₁ -C ₄₎ alkilaminosulfonilamino, and optionally fused to a 5-membered heterocyclic ring containing in the ring two oxygen or two nitrogen atoms,

R ³ is hydrogen or C ₁ -C ₄ alkyl optionally substituted with a hydroxy, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylthio group,

R ⁴ means hydrogen or C ₁ -C ₄ alkyl,

R ⁵ means a quinolinyl, isoquinolinyl or oxo-dihydroisoquinolinyl group, optionally fused to a 5-membered heterocyclic group containing two oxygen atoms or two nitrogen atoms in the ring, and optionally substituted with one or more substituents selected from the range of halogen, cyano, carboxy, hydroxy, C ₁ -C ₄ alkyl, hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ alkoxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ alkylthio (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkylcarbonyl, a group of the formula —N (R ⁶ ) R ⁷ or phenyl optionally substituted th one or more substituents selected from halogen or C ₁ -C ₄ alkoxy, and

R ⁶ and R ⁷ each independently mean hydrogen or C ₁ -C ₄ alkyl optionally substituted with a hydroxy or alkoxy group, or one of R ⁶ and R ⁷ means hydrogen and the other means C ₁ -C ₄ alkylcarbonyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached mean a 5- or 6-membered heterocyclyl group containing one or two nitrogen atoms in the ring and optionally an oxygen atom.

More preferred are compounds of formula I, where

R ¹ means hydrogen or C ₁ -C ₄ alkyl,

R ² means hydrogen, C ₁ -C ₈ alkyl, hydroxy (C ₁ -C ₈ ) alkyl or C ₁ -C ₄ alkylcarbonyloxy (C ₁ -C ₈ ) alkyl, C ₂ -C ₄ alkenyl, C ₃ -C ₆ cycloalkyl (C ₁ -C ₄ ) alkyl, heterocyclyl (C ₁ -C ₄ ) alkyl, where the heterocyclyl group means a 5-membered heterocyclyl group containing one nitrogen or oxygen atom in the ring, phenyl (C ₁ -C ₄ ) alkyl, where phenyl optionally substituted with one or two substituents selected from the series C ₁ -C ₄ alkoxy, amino, C ₁ -C ₄ alkylcarbonylamino, chloro, bromo, C ₁ -C ₄ alkylsulfonylamino or di (C ₁ -C ₄ ) alkylaminosulfonylamino, and optionally fused from 5- lennym heterocycle containing in the ring two oxygen atoms,

R ³ means hydrogen or C ₁ -C ₄ alkyl,

R ⁴ means hydrogen or C ₁ -C ₄ alkyl,

R ⁵ means a quinolinyl group of the formula II, an isoquinolinyl group of the formula III or an oxo dihydroisoquinolinyl group of the formula IIIA, where R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are} each independently selected from the series hydrogen, halogen, cyano, carboxy, hydroxy C ₁ -C ₄ alkyl; hydroxy (C ₁ -C ₄ ) alkyl; C ₁ -C ₄ alkoxy (C ₁ -C ₄ ) alkyl; C ₁ -C ₄ alkylthio (C ₁ -C ₄ ) alkyl; C ₁ —C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkylcarbonyl, a group of the formula —N (R ⁶ ) R ⁷ or phenyl optionally substituted with one or two substituents selected from halogen or C ₁ -C ₄ alkoxy, or R ¹¹ and R ¹² together with at the carbon ohms to which they are attached mean a 5-membered heterocyclic group containing two oxygen atoms in a cycle,

and R ⁶ and R ^{7 are} each independently hydrogen or C ₁ -C ₄ alkyl optionally substituted with a hydroxy or alkoxy group, or one of R ⁶ and R ⁷ is hydrogen and the other is C ₁ -C ₄ alkylcarbonyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached means a 6-membered heterocyclyl group containing one or two nitrogen atoms in the cycle, or one nitrogen atom and one oxygen atom.

Of the above preferred compounds, in particular, compounds in which R ⁵ is an isoquinolinyl group of formula III, where R ⁸ is hydrogen, C ₁ -C ₄ alkyl, halogen, cyano, —N (R ⁶ ) R ⁷ , where R ⁶ and R ⁷ each independently means C ₁ -C ₄ alkyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached mean a 6-membered heterocyclyl group containing one or two nitrogen atoms or one atom in a cycle nitrogen and one oxygen atom, or phenyl substituted with one or two C ₁ -C ₄ alkoxy groups; R ⁹ and R ¹⁰ each independently mean hydrogen, C ₁ -C ₄ alkyl or halogen; R ¹¹ and R ¹² each independently mean hydrogen, halogen, cyano, carboxy, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₂ -C ₄ alkynyl, or R ¹¹ and R ¹² together with carbon atoms, to which they are attached means a 5-membered heterocycle containing two oxygen atoms in a cycle; and R ¹³ means hydrogen or halogen.

First of all, the compounds of formula I described in the examples are particularly preferred. Of these compounds, the compounds described in Examples 7, 10, 15, 35, 45, 49, 55, 60, 68, and 70 are more preferred.

The compounds of formula I may exist in the form of salts, especially pharmaceutically acceptable salts. Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example, aliphatic monocarboxylic acids, such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids, such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids, such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, parachlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids you like ortogidroksibenzoynaya acid, parahydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. Pharmaceutically acceptable base salts of the compounds of formula I, where R ³ is hydrogen, include metal salts, especially alkali and alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, as well as ammonium or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts can be obtained from free compounds of formula I or other salts of compounds of formula I by known methods.

In addition, the present invention relates to a method for producing compounds of formula I in the form of a free compound or its salt, which includes

1) (a) dehydration of a compound of the formula

where R ¹ , R ² , R ⁴ and R ⁵ have the meanings indicated above; or

(b) to obtain a compound of formula I in free or salt form, where R ³ is alkyl optionally substituted with a hydroxy, alkoxy or alkylthio group, reacting a compound of formula I in free or salt form with an appropriate alkylating agent, or

(c) to obtain a compound of formula I in free or salt form, where R ² is aralkyl substituted in the aryl ring with an alkylsulfonylamino or dialkylaminosulfonylamino group, reacting a compound of formula I in salt form, where R ² is aralkyl substituted with amino, respectively with alkylsulfonyl halide or dialkylaminosulfonyl halide; or

(d) to obtain a compound of formula I in free form or in salt form, where R ² is hydroxy-substituted alkyl, hydration of a compound of formula I, where R ² is alkenyl; or

(e) to obtain a compound of formula I in free or salt form, where R ² is alkyl substituted with an alkylcarbonyloxy group, the corresponding esterification of a compound of formula I, where R ² is hydroxy-substituted alkyl; or

(e) to obtain a compound of formula I in free form or in salt form, where R ² is aralkyl substituted in the aryl ring by an amino group, hydrolysis of a compound of formula I, where R ² is aralkyl substituted in the aryl ring by an acylamino group; or

(g) to obtain a compound of formula I in free or salt form, where R ⁵ is quinolinyl or isoquinolinyl substituted with a hydroxy group, dealkylation of a compound of formula I where R ⁵ is respectively quinolinyl or isoquinolinyl substituted with an alkoxy, especially methoxy ; or

(h) to obtain a compound of formula I in free or salt form, where R ⁵ is quinolinyl or isoquinolinyl substituted by halogen, halogenating a compound of formula I, where R ⁵ is respectively quinolinyl or isoquinolinyl containing in the ring an unsubstituted carbon atom available for halogenation; or

(i) to obtain a compound of formula I in free or salt form, where R ² is a cyclopropyl group optionally substituted with alkyl, the introduction of a compound of formula I, where R ² is alkenyl, in a Simmons-Smith cyclopropanylation reaction; and

2) isolation of the resulting product of formula I in free form or in salt form.

Method (a) can be carried out by heating or by reaction with an inorganic or organic base. The reaction can be carried out in an organic or in an aqueous solvent or in a mixed aqueous-organic medium. The reaction with the base can be carried out at ambient temperature or preferably at elevated temperature. The reaction is preferably carried out by treating with an aqueous solution of an alkali metal hydroxide in alcohol at an elevated temperature, for example, as described below in the examples. A compound of formula IV preferably means a compound wherein R ⁵ is a group of formula II or III. Compounds of formula IV can be prepared by reacting a compound of formula

where R ¹ and R ² have the meanings indicated above, with a compound of the formula

or a derivative thereof capable of forming an amide bond, wherein R ⁴ and R ⁵ are as defined above. The reaction can be carried out by treating a carboxylic acid of formula VI with a condensing agent leading to the formation of a peptide bond to form an in situ activated ester or mixed anhydride, followed by treatment with a compound of formula V in an organic, e.g., bipolar, aprotic solvent, or in a mixed aqueous-organic solvent ( e.g. chlorinated hydrocarbon). The latter reaction can be carried out at a temperature below room temperature, at room temperature or at an elevated temperature, preferably at ambient temperature. Preferably, the acid of formula VI is treated with a carbodiimide derivative in the presence of hydroxybenzotriazole, and optionally a base, or a salt of benzotriazolyl (trisdialkylamino) oxyphosphonium. The resulting intermediate compound is preferably treated with a compound of formula V in a bipolar aprotic solvent, or in a mixed solvent of chlorinated hydrocarbon / water at room temperature. These methods are described below in the examples.

Compounds of formula V can be prepared by reducing a compound of formula

where R ¹ and R ² have the meanings indicated above.

Recovery is carried out using known methods, for example, by treating a compound of formula VII with a reducing agent in an organic or aqueous solvent. The reaction can be carried out at ambient temperature or preferably at elevated temperature. Preferred reducing agents are alkali metal dithionites in an aqueous medium or hydrogen in the presence of a noble metal catalyst. More preferably, sodium dithionite is reduced in an aqueous solution at 80-90 ° C.

Compounds of formula VII can be prepared by nitrosation of a compound of formula

where R ¹ and R ² have the meanings indicated above, for example, an organic or inorganic nitrosating agent in an organic, aqueous or mixed aqueous-organic solvent. Nitrosation can be carried out by known methods at a temperature below room temperature, at room temperature or at an elevated temperature, preferably alkali metal nitrite, such as sodium nitrite, in the presence of an acid such as acetic acid, at lower or room temperature, preferably in a mixed aqueous-alcoholic medium, such as aqueous ethanol.

Compounds of formula VIII can be prepared by the reaction of a compound of formula

where R ² has the meanings indicated above, with an inorganic or organic base for cyclization, and then, if R ¹ means optionally substituted alkyl, by reaction with an alkylating agent. The cyclization reaction is carried out using conventional methods. Typically, the reaction is carried out in an aqueous, organic or mixed aqueous-organic solvent. The reaction can be carried out at room temperature or preferably at elevated temperature. The base is preferably used alkali metal hydroxide, especially sodium hydroxide, which preferably reacts in an aqueous-alcoholic environment, preferably at elevated temperatures, for example at 80-90 ° C. The optional alkylation step can be carried out using known methods, for example, in the presence of an inorganic or organic base, for example in an aqueous, organic or mixed aqueous-organic solvent. Alkylation can be carried out at a temperature below room temperature or preferably at room or elevated temperature. Preferred alkylating agents are alkyl iodides or, in particular, dialkyl sulfates. Preferred bases are alkali metal hydroxides in aqueous-alcoholic solvents, in particular aqueous ethanol.

Compounds of formula IX can be prepared by reacting a compound of formula

with cyanoacetic acid or an amide derivative thereof capable of forming an amide bond, such as an ester or an acid halide, preferably with an acid or ethyl ester thereof. The reaction can be carried out using known methods, for example, in an organic solvent, preferably in an anhydride such as acetic anhydride, at room or preferably at elevated temperature, for example 65-70 ° C.

Compounds of formula X can be prepared using conventional methods, for example, by reacting an R ² NCO isocyanate with gaseous or aqueous ammonia or an R ² NH ₂ amine with a metal cyanate, for example, as described below in the examples.

Compounds of formula VIII, wherein R ¹ is alkyl optionally substituted with a hydroxy, alkoxy or alkylthio group, and R ² is as defined above and does not mean hydrogen, can be prepared by hydrogenolysis of a compound of formula

wherein R ¹ is alkyl optionally substituted with a hydroxy, alkoxy or alkylthio group, and R ² is as defined above and does not mean hydrogen, and Ar is phenyl optionally substituted with one or more C ₁ -C ₄ alkoxy groups, preferably methoxy. Hydrogenolysis can be carried out in a known manner, for example by treating with hydrogen or a hydrogen source in the presence of a metal catalyst, such as platinum, or preferably a palladium catalyst. The reaction can be carried out in an organic solvent at room or elevated temperature. Preferably, the hydrogenolysis is carried out using palladium black in formic acid, for example, as described below in the examples.

Compounds of formula XI can be prepared by reacting a compound of formula

where R ¹ and R ² have the meanings given above for formula XI, with a compound of the formula ArCH ₂ NH ₂ , where Ar has the meanings given above. The reaction is carried out in a known manner, for example, in an organic solvent, preferably in an alcohol, such as n-butanol, at room or elevated temperature, or similarly as described below in the examples.

Compounds of formula XII can be prepared by reacting a compound of formula

where R ¹ has the meanings given above for formula XI, with a compound of the formula R ² X, where R ² has the meanings specified above for formula XI, and X is halogen or hydroxy, when X is hydroxy, the reaction is carried out in the presence of activating reagents, preferably azodicarboxylate, such as di-tert-butylazodicarboxylate, in admixture with triarylphosphine, such as diphenylpyridylphosphine. The reaction can be carried out in an organic solvent, preferably in an ether, such as dioxane, at a temperature below room temperature, or preferably at ambient temperature or elevated temperature. The reaction can be carried out according to the method described in the article Mitsonobu, Synthesis, 1 (1981), or similarly as described below in the examples. The compounds of formula XIII are known or can be obtained by known methods.

Compounds of formula VI can be prepared, for example, (I) from benzaldehyde or substituted benzaldehyde using the method described in Dyke et al., Tetrahedron, 24, 1467 (1968), or (II) from optionally substituted, N-protected 1 , 2-dihydroisoquinoline by reaction with 2-oxocarboxylic acid using the method described by Dyke et al. Tetrahedron 24, 1467 (1968), optionally followed by conversion of the resulting carboxylic acid to methyl ether and then to an alkali metal salt according to the method described in J. March, Advanced Organic Chemistry, 4 ^th Edition, Wiley, New York (1992 ), pp. 393 and 378, or (III) from optionally substituted quinoline or isoquinoline by reaction with a reducing agent in the form of a hydride, followed by reaction with 2-oxocarboxylic acid ester according to the method described in Minter et al., J. Org. Chem., 53, 2653 (1988), or (IV) by the introduction of substituents in the N-containing acid cycle of the acid of formula VI according to the method described in articles by Janin and Biagani, Tetrahedron, 39, 10305 (1993) or Ford et al., J. Med. Chem., 28, 164 (1985).

Some of the preferred compounds of formula VI can be prepared as shown in the schemes below.

(I) According to the sequence of reactions

where R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the meanings indicated above. Steps (a) - (c) can be carried out by known methods, for example, using the method described in the article by Dyke et al., Tetrahedron, 24, 1467 (1968), or similarly as described below in the examples.

(II) According to the sequence of reactions

where R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the meanings indicated above. Stage (g) - (g) can be carried out by known methods, for example stage (g) using the method described in the article by Katayama et al., Chem. Pharm. Bull., 28, 2226 (1980), stage (e) using the method described in the article by Dyke et al., Tetrahedron, 24, 1467 (1968), stage (e) and (g) according to the method described in book J .March, Advanced Organic Chemistry, 4 ^th Edition, Wiley, New York (1992), pp. 393 and 378, or similarly as described below in the examples.

(III) According to the reaction

for example, treating compound VIII with a reducing agent in the form of a hydride, followed by reaction with a 2-oxocarboxylic acid ester according to the method described by Minter et al., J. Org. Chem., 53, 2653 (1988), or similarly as described below in the examples.

(IV) Compounds of formula VI, where R ⁵ is a 4-isoquinolinyl group substituted at position 1, are prepared by the following reaction sequence

where R ⁴ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the meanings indicated above. Stage (h) - (l) can be carried out by known methods, for example stage (h) - (k) according to the method described in the article by Janin and Biagani, Tetrahedron, 39, 10305 (1993), and stage (l) using the method described in J.March, Advanced Organic Chemistry, 4 ^th Edition, Wiley, New York (1992), p. 378, or similarly as described below in the examples.

(V) Compounds of formula VI, where R ⁵ is an isoquinolinyl group of formula III, where R ⁸ is a cyano group, are prepared according to the following reaction sequence

where R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the meanings indicated above. Stage (m) - (o) can be carried out by known methods, for example stage (m) and (n) according to the method described in the article Ford and others, J. Med. Chem., 28, 164 (1985), and stage (o) according to the method described in the book cited above J.March, p. 378.

(VI) Compounds of formula VI, where R ⁵ is an oxo dihydroisoquinolinyl group, are prepared according to the following reaction sequence

where R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the meanings indicated above. Steps (p) and (p) can be carried out by known methods, for example, according to the method described in Holzgrabe, Arch. Pharm. (Weinheim, Germany), 321, 767 (1988), or similarly as described below in the examples.

(VII) Compounds of formula VI, where R ⁵ means a quinolinyl group, obtained by the reaction

where R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are as defined above, which is carried out in a known manner, for example by treatment with a strong base, preferably an alkali metal dialkylamide such as lithium diisopropylamide, followed by treatment with carbon dioxide, for example, according to the method used by Brown and Curless, Tetrahedron Lett., 27,6005 (1986), or similarly as described below in the examples.

(VIII) Compounds of formula VI, where R is a 4-isoquinolinyl group, are prepared according to the following reaction sequence

where R ⁸ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ have the meanings indicated above. Steps (c) to (h) can be carried out by known methods, for example, step (c) is carried out by treating with a carboxyethyltriarylphosphonylide, preferably a carboxyethyltriphenylphosphonylide in an organic solvent, preferably in an ether or hydrocarbon, especially in toluene, at low, high or preferably at ambient temperature environment; stage (t) is carried out by treatment with nitromethane in the presence of an inorganic base or preferably an amine, in particular tetramethylguanidine, for example in the presence of a solvent or preferably in the absence of a solvent, at low, room or preferably elevated temperature, for example at 60-80 ° C; step (s) is carried out by treating with a reducing agent, preferably a tin (II) salt, in particular a tin (II) chloride hydrate, in an aqueous or preferably organic solvent, preferably in an alcohol such as ethanol, at reduced, room or preferably elevated temperature, for example, at reflux; stage (f) is carried out by treating with an acid halide or anhydride, preferably acid chloride, an acid R ⁸ COOH, at elevated or preferably lower or room temperature, for example at a temperature of from 0 ° C to room temperature, in an aqueous or preferably organic solvent, especially in a chlorinated a hydrocarbon such as dichloromethane, preferably in the presence of a base, in particular an amine, such as triethylamine; step (x) is carried out by treatment with a phosphorus (V) halide or oxyhalide, preferably phosphorus pentachloride or phosphorus oxychloride, preferably in an organic solvent such as a hydrocarbon or nitrile, in particular acetonitrile, preferably at room or, above all, elevated temperature, for example refluxing; step (c) is carried out by treatment with a noble metal catalyst, preferably palladium, preferably in an organic solvent, in particular a hydrocarbon such as decalin, preferably at elevated temperature, for example, by refluxing; step (h) is carried out by treatment with an alkali metal hydroxide, preferably lithium or sodium hydroxide, in an organic, aqueous or mixed aqueous-organic solvent, preferably in THF / water, at a reduced, elevated or preferably room temperature; specific methods for performing steps (c) to (h) are described in the examples below.

(IX) According to the sequence of reactions

where R ⁹ , R ¹¹ , R ¹² and R ¹³ are as defined above, Ac is an acyl group, and Y is halogen. Steps (w) - (y) can be carried out by known methods, for example, step (w) is carried out by reaction with a halogenating agent, for example bromine or N-halogenosuccinimide, preferably N-chlorosuccinimide, for example, as described in J.March and cited above. dr. p. 513; stage (s) is carried out by reaction with a reducing agent, for example metal hydride, in the presence of an acylating agent, for example acetic anhydride, for example, as described in the article cited by Katayama et al .; step (e) is carried out by reaction with 2-oxocarboxylic acid, preferably glyoxylic acid, in the presence of a mineral acid, for example, as described in Dyke et al., Tetrahedron, 24, 1467 (1968); stage (s) is carried out by treatment with a reducing agent, for example, as described in the book cited above J.March et al., p. 566; or similarly as described below in the examples.

As shown below, some compounds of formula V, including intermediates 1-10, as well as some compounds of formula VI, including intermediates 20-48, are new.

Option (b) can be carried out in a known manner, for example, by reacting a compound of formula I, where R ³ is hydrogen, with an appropriate alkylating agent, preferably an alkyl iodide or dialkyl sulfate, such as a compound of formula R ³ I or (R ³ ) ₂ SO ₄ , where R ³ means C ₁ -C ₄ alkyl. The reaction can be carried out in the presence of an inorganic or organic base, for example in an aqueous, organic or mixed aqueous-organic solvent. Alkylation can be carried out at a reduced temperature, or preferably at room or elevated temperature. Preferred bases are alkali metal carbonates. Preferred solvents are organic bipolar aprotic solvents, especially N, N-dimethylformamide.

Option (c) can be carried out using known sulfonylation methods, for example in the presence of an organic or inorganic base, preferably a tertiary organic base, such as pyridine. The reaction is carried out at a reduced, room or preferably elevated temperature. Preferred are the methods described below in the examples.

Option (g) can be carried out using known methods, for example, by treating a compound of formula I, where R ² is alkenyl, with a hydroboarding agent, followed by oxidation in an alkaline medium. Hydroboration can be carried out at reduced or preferably at room or elevated temperature. Preferred hydroboration agents are dialkylboranes, such as 9-borabicyclo [2.2.0] nonane, the reaction with which is preferably carried out under reflux. The oxidation is preferably carried out with hydrogen peroxide in the presence of an alkali metal hydroxide, preferably sodium hydroxide, at a temperature of preferably 40-60 ° C.

Option (d) can be carried out using known esterification methods, for example, by reacting a compound of formula I, where R ² is hydroxy, with a carboxylic acid or its acid halide, preferably acid chloride, in the presence of an organic or inorganic base, at a reduced or preferably room or elevated temperature (for example, at 40-60 ° C). Preferred bases are tertiary organic bases such as pyridine.

Option (e) may be carried out using known methods for converting the acylamino group to amino, for example by treating with a mineral acid such as sulfuric or preferably hydrochloric acid. The reaction is preferably carried out in a mixed aqueous organic solvent, such as aqueous ethanol, at room or preferably elevated temperature, especially when refluxed.

Option (g) can be carried out using known dealkylation methods, for example, by reaction with HBr or HI, usually at elevated temperature, preferably by heating in concentrated hydrobromic acid, for example, as described below in the examples.

Option (h) can be carried out using known halogenation methods, for example, by reaction with bromine or chlorine in a solvent such as acetic acid. Typically, the reaction is carried out at room temperature, for example, as described below in the examples.

Option (s) can be carried out using well-known Simmons-Smith reaction techniques, for example, by reaction with diethylzinc and chloriodomethane. Typically, the reaction is carried out in an organic solvent, preferably in a halogenated hydrocarbon, at room temperature, for example, as described below in the examples.

The compounds of formula I in free form can be converted into salt form and again into free form by known methods. Compounds in free or salt form can be prepared in the form of hydrates or solvates containing the solvent used in the crystallization. The compounds of formula I in free or salt form may be isolated from the reaction mixtures by conventional methods. Mixtures of isomers can be separated into individual isomers, for example enantiomers, in a conventional manner, for example fractional crystallization.

The compounds of formula I in free form or in the form of a pharmaceutically acceptable salt, hereinafter referred to as agents of the invention, are used as pharmaceutical preparations. First of all, these compounds inhibit 3 ', 5'-cycloguanosine monophosphate phosphodiesterase (cGMP-PDE, cGNP-PDEs), especially PDE5. The agents of the invention are selective PDE5 inhibitors, in particular they exhibit a high selectivity for inhibiting PDE5 compared to inhibiting other types of phosphodiesterases, especially PDE1 and PDE6, having a limited spectrum of side effects.

In addition, the agents of the invention have a satisfactory duration of action, and many of them have a rapid onset of action. The inhibitory properties of the agents of the invention are determined by the following procedure.

Method for determination of PDE5 inhibitory activity

A 10 mM solution of the test compound in DMSO was diluted 100 times with 20% (v / v) aqueous DMSO, and 100 μM stock solution was obtained. Then, the initial solution was diluted a second time with 20% (v / v) aqueous DMSO, and ten solutions were obtained with a concentration in the range from 10 μM to 0.00051 μM. In a selected well of a 96-well microtiter plate (Optiplate, Packard), 10 μl of each of the resulting solutions was added. To determine complete binding, 10 μl of a 20% (v / v) aqueous DMSO solution is added to other selected wells. To determine nonspecific binding, 10 μl of sildenafil working solution, which is prepared from a 10 mM solution in 100% DMSO by 20-fold dilution with 20% (v / v) aqueous DMSO, is added to other selected wells of the plate. To all wells containing a solution of the analyte, aqueous DMSO or a solution of sildenafil, add 80 μl of a solution of the mixture for analysis, which is prepared by mixing a buffer solution for analysis of PDE (2 ml), 2 ml of an aqueous solution of bovine serum albumin (BSA) (concentration 5 mg / ml), 0.2 ml of a 75 μM cGMP sodium salt solution, 10 μl of a 3H-cGMP solution (Amersham) and 11.8 ml of distilled water. To obtain a buffer solution for PDE analysis, 7.56 g of Tris (base) is dissolved in 800 ml of water, 1 M aqueous solution of MgCl ₂ (10.325 ml), 0.5 M EDTA solution (4.25 ml), 1N are added. hydrochloric acid to a pH of 7.5 and adjusted with water to a final volume of 1 liter. A solution of human PDE5 partially purified from human platelets (11 μl containing 0.017 units of PDE5 / MA, with 1 unit hydrolyzing 3 ′, 5′-cGMP to 5′-GMF at a rate of 1.0 μmol / min at pH 7 , 5 and 37 ° C) in 20 mM HEPES, pH 7.4, containing 100 mM NaCl, 10% (v / v) glycerin, 1 mM benzamidine and 2 mM dithiothreitol, diluted 200 times with an enzyme buffer solution, to obtain which to a solution of 1.21 g of Tris (base) in 800 ml of water add 2 ml of a 0.5 M solution of EDTA, 1N. HCl to pH 7.5, and adjusted with water to a final volume of 1 liter. 10 μl of a diluted PDE5 solution is added to all wells containing the analyte solution, aqueous DMSO or sildenafil solution and the plate is incubated at room temperature for 1 hour. Then, 50 μl of a suspension of yttrium silicate granules (PDE Yttrium silicate SPA) are added to each well. , Amersham) in 28 ml of water, the plate is incubated for another 20 minutes, and then closed with Top Seak-S film (Packard) in accordance with the manufacturer's recommendations. The number of pulses is recorded on a pulse counter (Canberra Packard Top Count) (1 well / min), determining the degree of inhibition of binding of PDE5 to the sorbent granules. The concentration of the analyte, in which there is an inhibition of binding of PDE5 to the sorbent by 50% (IC ₅₀ ), is determined according to the graph of the degree of inhibition versus concentration in the usual way.

When analyzed by this method, the IC ₅₀ value for the compounds described in the examples below is from 0.0005 μM to 10 μM. For example, the IC ₅₀ value for the compounds described in examples 7, 10, 15, 35, 45, 49, 55, 60, 68 and 70 is 0.007 μM, 0.01 μM, 0.006 μM, 0.01 μM, 0.002 μM , 0.0037 μM, 0.0055 μM, 0.0028 μM, 0.007 μM, 0.009 μM, respectively.

Due to the inhibition of PDE5, the agents of the invention can be used to treat conditions mediated by PDE5. The treatment of the invention may be symptomatic or prophylactic.

Thus, the agents of the invention can be used to treat sexual dysfunction, including erectile dysfunction in men and sexual dysfunctions in women, such as premature birth, dysmenorrhea, benign prostatic hyperplasia, infravesical obstruction syndrome, incontinence, persistent, unstable angina and a type of angina pectoris ( Prinzmetal), hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions such as decreased patency of blood vessels, for example, after percutaneous nsluminal coronary vascular reconstruction, peripheral vascular disease, bronchitis, asthma, allergic rhinitis, glaucoma, tinnitus, diseases characterized by impaired intestinal motility, for example, irritable bowel syndrome (mucous colitis), preeclampsia (late pregnancy toxicosis), Kawasaki syndrome, tolerance nitrate, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, al petsiya, esophagitis (nutcracker), anal fissure and hypoxic vasoconstriction.

The agents of the invention are primarily of interest for use in the treatment of sexual dysfunction, especially erectile dysfunction.

In accordance with the foregoing, the invention also relates to a method for treating a condition mediated by PDE5, for example, the aforementioned disorder, preferably sexual dysfunction, especially male erectile dysfunction, the method comprising administering to a subject, especially a person in need of treatment, an effective amount of a compound of formula I in free form or in the form of a pharmaceutically acceptable salt. In addition, the invention relates to the use of compounds of formula I, in free form or in the form of a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of a condition mediated by PDE5, for example the aforementioned condition, preferably sexual dysfunction, especially male erectile dysfunction.

The agents of the invention may be administered by any suitable route, for example, by the oral route, in the form of a tablet, capsule, solution or suspension; in a parenteral manner, for example, by the intravenous, intracavernous, intramuscular or subcutaneous route; intranasally, for example in the form of an aerosol or aqueous dispersion; inhalation, for example in the form of an aerosol, sprayed aqueous dispersion or dry powder; in a buccal or sublingual manner, for example in the form of a tablet or lozenge; topically to the skin, for example in the form of a cream or ointment; or rectally, for example in the form of a suppository.

The invention further relates to pharmaceutical compositions comprising, as an active ingredient, a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, optionally in admixture with a pharmaceutically acceptable diluent or carrier. Such compositions can be prepared using appropriate excipients and methods known in the art of pharmacy. Thus, oral dosage forms may include tablets and capsules. Compositions for inhalation may include an aerosol or other nebulized or dry powder form. Topical skin compositions may include creams, ointments, or gels.

The agents of the invention can also be used in combination with other PDE5 inhibitors or other therapeutic agents suitable for treating sexual dysfunction, preferably male erectile dysfunction, for example with α-adrenergic receptor antagonists such as phentolamine methanesulfonate, with dopamine agonists such as apomorphine or donors NO, such as L-arginine. The agent of the invention may be mixed with a concomitant therapeutic agent in a pharmaceutical composition, or may be administered separately, before, simultaneously with or after administration of a concomitant agent.

The present invention is illustrated by the following examples.

Intermediates of formula V are prepared as described below.

Intermediate 1

To a solution of conc. hydrochloric acid (250 ml) in water (1.9 L) add methylallylamine (211 g, 2.97 mol), and then potassium cyanate (240 g, 2.97 mol) is added in portions. The reaction mixture was heated at 80 ° C for 2 hours, and then cooled and evaporated to give (2-methylallyl) urea (244.5 g), _mp 114-115 ° C. Urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride (536 ml), the reaction mixture is heated at 70 ° C for 1 h, cooled to 0 ° C and diluted with ether. The resulting solid was separated by filtration, washed with ether, suspended in water (2.2 L) and heated to 75 ° C. Then, a 2 M aqueous sodium hydroxide solution was added in portions over 30 minutes, maintaining the pH in the range of 8-9.5. The reaction mixture was cooled to room temperature, treated with acetic acid (12 ml) and cooled to 10 ° C., the resulting solid was filtered off, washed with cold water and dried to give 6-amino-1- (2-methylallyl) -1H- pyrimidine-2,4-dione, t _pl. 267-269 ° C. To a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 L), uracil (253 g, 1.40 mol) is added and an exothermic reaction is carried out, after which the reaction mixture is cooled to 20 ° C. Then, dimethyl sulfate (196 ml, 2.06 mol) was added in portions over 1 h, the reaction mixture was incubated overnight, cooled to 5 ° C and the solid was separated by filtration to obtain 6-amino-3-methyl-1- ( 2-methylallyl) -1H-pyrimidine-2,4-dione, t _pl. 162-163 ° C. Methyluracil (165 g, 0.85 mol) is suspended in water (1.55 L) and conc. hydrochloric acid (72 ml). Then, a solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) was added dropwise over 30 minutes, and the reaction mixture was stirred at 20 ° C. for 3 hours. The solid was separated by filtration and washed successively with water. methanol and ether, while getting 6-amino-3-methyl-1- (2-methylallyl) -5-nitroso-1H-pyrimidine-2,4-dione, t _pl. 213 ° C (decomp.). Nitrosouracil (190 g, 0.85 mol) was suspended in water (950 ml), heated to 85 ° C and sodium dithionite (85%, 347.2 g, 1.69 mol) was added portionwise. After cooling to room temperature, the solid was separated by filtration, whereby 5,6-diamino-3-methyl-1- (2-methylallyl) -1H-pyrimidine-2,4-dione, _mp. 152-153 ° C.

Intermediate 2

6-amino-3-methyl-1- (3-nitrosobenzyl) -1H-pyrimidin-2,4-dione, [MH] ^- 275, obtained from (3-nitrobenzyl) urea (see J. Med. Chem ., 39, 1924 (1996)) according to the general procedure for preparing intermediate 1. A suspension of this compound (4.88 g, 17.7 mmol) and 10% Pd / C (0.484 g) in ethanol (200 ml) are hydrogenated under pressure 1 atm for 1.5 hours. The reaction mixture was filtered through a celite pad and evaporated to give 6-amino-1- (3-aminobenzyl) -3-methyl-1H-pyrimidine-2,4-dione acetate, [M -H] ^- 245. To a cooled (0 ° C) suspension of 6-amino-1- (3-aminobenzyl) -3-methyl-1H-pyrimidin-2,4-dione acetate (5.01 g, 16.35 mmol) ) to the feast Idine (50 ml) was added acetic anhydride (1.85 ml, 19.57 mmol), the reaction mixture was warmed to room temperature, stirred for 6 hours and the solvent was evaporated. The residue was triturated in water, the solid was separated by filtration, dried, and N- [3- (6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) phenyl was obtained ] acetamide, ¹ H-NMR (400 MHz, DMSO): δ 2.00 (s, 3H), 3.09 (s, 3H), 4.72 (s, 1H), 5.02 (s, 2H) 6.75 (s, 2H); 6.88 (d, J6 1H); 7.25 (t, J6 1H); 7.30 (s, 1H); 7.55 (d, J6 1H).

N- [3- (5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) phenyl] acetamide, [MH] ⁺ 304, obtained from the indicated compound according to the General method for producing intermediate compound 1.

Intermediate 3

6-amino-3-methyl-1- (4-nitrobenzyl) -1H-pyrimidine-2,4-dione, [MH] ⁺ 277, is obtained from (4-nitrobenzyl) urea according to the general procedure for the preparation of intermediate derivative 1. To solution 6-amino-3-methyl-1- (4-nitrobenzyl) -1H-pyrimidine-2,4-dione (19.08 g, 69.0 mmol) in acetic acid (300 ml) add a solution of calcium chloride (4, 94 g, 45 mmol) in water (100 ml). Then, with external cooling (in the bath), zinc dust (58.8 g, 900 mmol) is added in portions, the reaction mixture is stirred at room temperature for 1.5 hours, filtered through a layer of celite, which is washed thoroughly with ethanol and acetic acid. The combined filtrate was evaporated, the residue was washed, and 6-amino-1- (4-aminobenzyl) -3-methyl-1H-pyrimidin-2,4-dione acetate, [M-3H] ^- 243 was obtained. C cooled (0 ° C) suspensions of 6-amino-1- (4-aminobenzyl) -3-methyl-1H-pyrimidin-2,4-dione acetate (17.0 g, 69.0 mmol) in pyridine (260 ml) add acetic anhydride ( 7.2 ml, 76.0 mmol), the reaction mixture was warmed to room temperature, stirred for 6 hours and the solvent was evaporated. The residue was triturated in water, the solid was filtered off and dried, yielding N- [4- (6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) phenyl ] acetamide, [MH] ⁺ 289. N- [4- (5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl) phenyl] acetamide, [ MH] ⁺ 304, is obtained from the indicated compound according to the general procedure for the preparation of intermediate 1.

Intermediate 4

To a cooled suspension (0 ° C) of 6-chloromethyluracil (2.0 g, 12 mmol) in THF / dioxane (1: 1, 16 ml), 2-pyridyl diphenylphosphine (3.60 g, 13.7 mmol) and cyclobutanomethanol ( 1.3 ml, 13.8 mmol) and then di-tert-butyl azodicarboxylate (3.15 g, 13.7 mmol) is added. The reaction mixture was stirred at room temperature overnight, treated with 4 M HCl in dioxane (15 ml) and evaporated. The residue was taken up in dichloromethane, washed with 3.5 M HCl, dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography (eluting with dichloromethane / methanol, 100: 1) to give 6-chloro-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.70-2.0 (m, 6H), 2.60 (m, 1H), 3.20 (s, 3H), 4.00 (d, J7 2H), 5.78 ( s, 1H), which was dissolved in n-butanol (50 ml), veratrilamine (4 ml, 26.5 mmol) was added and the reaction mixture was refluxed for 16 hours. The solvent was evaporated, the residue was taken up in dichloromethane, washed with 1 M HCl, dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography (eluting with dichloromethane / methanol, 50: 1) to give 1-cyclobutylmethyl-6- (3,4-dimethoxybenzylamino) -3-methyl-1H-pyrimidine-2,4-dione, ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60-1.80 (m, 4H), 1.80-2.00 (m, 2H), 2.50 (m, 1H), 3.21 ( s, 3H), 3.80 (s, 6H), 3.85 (d, J7 2H), 4.11 (d, J5 1H), 4.25 (m, 1H), 4.84 (s, 1H ), 6.74 (s, 1H), 6.80 (s, 2H). Then this compound is dissolved in formic acid (50 ml), palladium black (0.26 g) is added, the reaction mixture is heated at 40 ° C for 21 hours, filtered through celite, evaporated, and the reaction product is purified by preparative HPLC, whereby 6-amino-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, M ⁺ 209, from which, according to the general procedure for the preparation of intermediate 1, 5,6-diamino-1-cyclobutylmethyl-3-methyl- 1H-pyrimidine-2,4-dione, retention time with HPLC 0.17 min (gradient of acetonitrile in water 30-95%, 4 min).

Intermediate 5

5,6-Diamino-3-methyl-1- (tetrahydrofuran-2-ylmethyl) -1H-pyrimidin-2,4-dione, t _pl. 115-116 ° C, obtained from (tetrahydrofuran-2-ylmethyl) urea (see Collect. Czech. Chem. Commun., 37, 2786 (1972)) according to the general procedure for the preparation of intermediate 1.

Intermediate 6

5,6-Diamino-3-methyl-1- (2-methylbutyl) -1H-pyrimidine-2,4-dione, t _pl. 163-165 ° C. is prepared using the general procedure for the preparation of intermediate 1.

Intermediate 7

5,6-Diamino-1-hexyl-3-methyl-1H-pyrimidin-2,4-dione is obtained from 6-amino-1-hexyl-1H-pyrimidin-2,4-dione (see J. Med. Chem ., 36, 1465 (1993)) using the general procedure for the preparation of intermediate 1, retention time at HPLC 6.01 min (gradient of acetonitrile in water 0-95%, 8 min).

Intermediate 8

5,6-Diamino-1- (3,4-dimethoxybenzyl) -3-methyl-1H-pyrimidin-2,4-dione, [M-H] ^- 305, obtained from (3,4-dimethoxybenzyl) urea (cm Farmaco, Ed. Sci., 32, 813 (1977)) using the general procedure for preparing intermediate 1.

Intermediate 9

5,6-Diamino-1-benzo [1,3] dioxol-5-ylmethyl-3-methyl-1H-pyrimidin-2,4-dione, t _pl. 183-186 ° C. are prepared using the general procedure for the preparation of intermediate 1.

Intermediate 10

5,6-Diamino-1- (2,4-dichlorobenzyl) -3-methyl-1H-pyrimidin-2,4-dione was prepared using the general procedure for preparing intermediate 1. ¹ H NMR (400 MHz, DMSO-d6) : δ 3.16 (s, 3H), 5.05 (s, 2H), 6.18 (s, 2H), 6.82 (d, J9 1H), 7.38 (d, J9 1H), 7 62 (s, 1H).

Other intermediates of formula V are prepared as described in the literature and shown below:

Bibliography

(1) Eur. J. Med. Chem., 25, 653 (1990)

(2) J. Med. Chem., 39, 2 (1996)

(3) FR 2531085

(4) Eur. J. Med. Chem.-Chim. Ther., 9, 313 (1974)

Intermediates of formula VI are prepared as described below:

The intermediate connection 20

A mixture of 3- (3,4-dimethoxyphenyl) -5-nitropentanoic acid ethyl ester (J. Med. Chem., 32, 1450 (1989)) (0.50 g, 1.68 mmol) and tin (II) chloride dihydrate (1.90 g, 8.4 mmol) in ethanol (10 ml) was refluxed for 2 hours, cooled to room temperature and evaporated. The crude product was transferred to dichloromethane (15 ml), cooled to 0 ° C, triethylamine (5 ml) was added, followed by 3,5-dimethoxybenzoyl chloride (0.404 g, 2.02 mmol). The reaction mixture was stirred at room temperature overnight, then evaporated, transferred to ethyl acetate, washed with water and dried over sodium sulfate. Evaporation and flash chromatography (elution with hexane / ethyl acetate, 1: 1) gave ethyl 4- (3,5-dimethoxybenzoylamino) -3- (3,4-dimethoxyphenyl) butyric acid, [MH] ⁺ 432. The obtained intermediate compound (0.200 g, 0.46 mmol) was transferred to acetonitrile (8 ml), phosphorus oxychloride (0.211 g, 1.38 mmol) was added and refluxed for 3 hours. After evaporation of the solvent, the residue was taken up in ethyl acetate, washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to give ethyl ether ir [1- (3,5-dimethoxyphenyl) -6,7-dimethoxy-3,4-dihydroisoquinolin-4-yl] acetic acid, [MH] ⁺ 414. The resulting intermediate compound (0.50 g, 1.21 mmol ) was dissolved in decalin (10 ml) and 10% Pd / C (50 mg) was added. The reaction mixture was heated at 190 ° C for 2.5 hours, then cooled to room temperature and diluted with dichloromethane. After filtering through celite, the combined filtrate and the washings were evaporated to give [1- (3,5-dimethoxyphenyl) -6,7-dimethoxyisoquinolin-4-yl] acetic acid ethyl ester, ¹ H NMR (400 MHz, CDCl ₃ ) : δ 1.18 (t, J7 3H), 3.78 (s, 6H), 3.80 (s, 3H), 3.90 (s, 2H), 3.99 (s, 3H), 4, 10 (q, J7 2H), 6.50 (d, J 0.5 1H), 6.75 (d, J 0.5 2H), 7.20 (s, 1H), 7.36 (s, 1H ), 8.40 (s, 1H). The resulting intermediate (0.30 g, 0.73 mmol) was dissolved in methanol (10 ml), a 1 M aqueous solution of lithium hydroxide (0.80 ml, 0.80 mmol) was added, and the reaction mixture was stirred overnight at room temperature. . After evaporation of methanol, 1 M HCl was added to pH 7, the resulting solid was filtered off and dried, yielding [1- (3,5-dimethoxyphenyl) -6,7-dimethoxyisoquinolin-4-yl] acetic acid.

The intermediate connection 21

A mixture of 3-isopropoxy-4-methoxybenzaldehyde (3.9 g, 20 mmol) and (ethoxycarbonylmethylene) triphenylphosphorane (6.96 g, 20 mmol) in toluene (100 ml) is refluxed for 2 hours, cooled to room temperature and evaporated. The crude product was transferred to dichloromethane and filtered through a plug of silica gel to give ethyl ester (E) -3- (3-isopropoxy-4-methoxyphenyl) acrylic acid, R _f 0.70 (TCX in hexane / ethyl acetate, 1: 1) . The resulting intermediate was dissolved in nitromethane (10 ml), 1,1,3,3-tetramethylguanidine (0.5 ml) was added and the reaction mixture was boiled at 70 ° C for 36 hours. The solvent was evaporated, the residue was taken up in ethyl acetate, washed with 2n. . HCl, water, brine, dried over sodium sulfate and evaporated. The crude product is purified by flash column chromatography (eluting with hexane / ethyl acetate, 4: 1) to give 3- (3-isopropoxy-4-methoxyphenyl) -4-nitrobutyric acid ethyl ester, ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (t, J7 3H), 1.38 (d, J7 6H), 2.75 (d, J6 2H), 3.90 (m, 1H), 4.10 (m, 2H ), 4.48-4.78 (m, 3H), 6.75-6.86 (m, 3H). The obtained intermediate compound is converted to [1- (3,5-diisopropoxyphenyl) -6-isopropoxy-7-methoxyisoquinolin-4-yl] acetic acid using the general procedure for the preparation of intermediate compound 20. The compound is characterized as ethyl ether, [MH] ⁺ 496.

The intermediate connection 22

A solution of 3-ethoxy-4-methoxybenzaldehyde (3.6 g, 20 mmol) in ethanol (15 ml) was added to 2,2-dimethoxyethylamine (21 mmol) and the mixture was refluxed for 2 hours. After cooling to room temperature sodium borohydride (0.794 g, 21 mmol) was added and the mixture was stirred at room temperature overnight. Ethanol was evaporated, water was added and extracted with ethyl acetate. The organic extracts are combined, washed with water, brine, dried over magnesium sulfate and evaporated to give (2,2-dimethoxyethyl) (3-ethoxy-4-methoxybenzyl) amine, [MH] ⁺ 270. Intermediate (2.70 g, 10 mmol) are suspended in 6N. HCl, glyoxylic acid (0.88 g, 12 mmol) was added and the mixture was heated at 100 ° C for 1 h. After cooling to room temperature, methanol (30 ml) was added, the mixture was filtered, and the obtained compound was identified as methyl ether, M ⁺ 276. The filtrate is treated with lithium hydroxide (10 mmol) in THF / methanol / water overnight. After evaporation of the solvents, the crude product is partitioned between water and dichloromethane. The aqueous phase is washed with dichloromethane and evaporated to dryness to give the lithium salt of (7-ethoxy-6-methoxyisoquinolin-4-yl) acetic acid, which is used to obtain xanthine without further identification.

The intermediate connection 23

A solution of ethyl ester (6,7-dimethoxyisoquinolin-4-yl) acetic acid (Tetrahedron, 29, 3881 (1973)) (1.668 g, 6.07 mmol) in chloroform (20 ml) is treated with portions of methachloroperoxybenzoic acid (1.153 g, 6 , 67 mmol) for 5 hours. The reaction mixture was washed with saturated sodium bicarbonate solution, brine, dried over MgSO ₄ and evaporated to give ethyl (6,7-dimethoxy-2-hydroxyisoquinolin-4-yl) acetic acid ( 1.71 g, 96%). All of the resulting product was dissolved in chloroform (30 ml), added to POCl ₃ (3 ml, 32.3 mmol) and refluxed for 2 hours. After evaporation, dichloromethane, ice water were added and the mixture was made basic with aqueous ammonia. The aqueous phase is then extracted with dichloromethane, the combined organic phases are washed with brine, dried over magnesium sulfate and evaporated to give ethyl (1-chloro-6,7-dimethoxyisoquinolin-4-yl) ethyl acetate. The resulting compound (0.50 g, 1.6 mmol) was suspended in 2 M sodium hydroxide (15 ml), ethanol (5 ml) was added and stirred at room temperature for 2 hours. Then the solvent was evaporated and the solution was acidified with conc. hydrochloric acid to pH 2, the resulting solid was separated by filtration and dried, to give (1-chloro-6,7-dimethoxyisoquinolin-4-yl) acetic acid. ¹ H NMR (400 MHz, DMSO-d6): δ 3.92 (s, 3H), 3.96 (s, 3H), 4.02 (s, 2H), 7.31 (s, 1H), 7 44 (s, 1H); 8.04 (s, 1H).

The intermediate connection 24

(2,2-Dimethoxyethyl) (3-methoxybenzyl) amine (Tetrahedron, 29, 3881 (1973)) is treated with pyruvic acid according to the general procedure for preparing intermediate 22 to give 2- (7-methoxyisoquinolin-4-yl) propionic hydrochloride acid, t _pl. 174-176 ° C. After treatment with gaseous HCl in ethanol, the hydrochloride salt of the corresponding ethyl ether is obtained, _mp. 190-192 ° C, which is reacted with methachloroperoxybenzoic acid and then with phosphorus oxychloride as described in the preparation of intermediate 23, whereby 2- (1-chloro-7-methoxyisoquinolin-4-yl) propionic acid ethyl ester , t _pl. 126-128 ° C. The resulting intermediate (47 g, 0.16 mol) was dissolved in ethanol (400 ml), 2N was added. sodium hydroxide (150 ml), heated at 60 ° C for 1 h and the solvent was evaporated. After crystallization from acetone, 2- (1-chloro-7-methoxyisoquinolin-4-yl) propionic acid is obtained, _mp 167-168 ° C.

The intermediate connection 25

To 2- (7-methoxy-2-hydroxyisoquinolin-4-yl) propionic acid ethyl ester (28 g, 0.10 mol), dimethyl sulfate (12.7 ml, 0.10 mol) is added in portions, and an exothermic reaction occurs with heating the mixture to 100 ° C. The reaction mixture was heated at 100 ° C for 2 hours, cooled to room temperature and dissolved in water (50 ml). Then, a solution of sodium cyanide (15 g, 0.31 mol) in water (90 ml) was added over 30 minutes with external cooling (in a bath) and the reaction mixture was stirred at room temperature for 3 hours. The crude product was extracted with chloroform, the extracts were washed saturated sodium bicarbonate solution, brine, dried over sodium sulfate and evaporated. After crystallization from 3n. HCl in ethanol / ether gives 2- (1-cyano-7-methoxyisoquinolin-4-yl) propionic acid ethyl ester hydrochloride, _mp 89-98 ° C, which is hydrolyzed to give an acid as described for intermediate 22, and used to produce xanthine without further purification.

The intermediate connection 26

To a solution of isoquinoline (1.64 g, 12.7 mmol) in THF (25 ml) was added dropwise a solution of sodium triethyl borohydride (1 M THF, 12.7 ml, 12.7 mmol) and the reaction mixture was stirred at room temperature for 1 h. Then, a solution of ethyl glyoxalate (1.43 g, 13.9 mmol) in toluene (preheated at 110 ° C. for 1.5 h) was added dropwise and kept at room temperature for 4 h. Then the reaction mixture was cooled to 0 ° C, add an aqueous solution of sodium hydroxide (0.5 M, 25.4 ml), hydrogen peroxide (30% aqueous solution, 12.7 ml) and mix for e 2 h. After which the mixture is acidified with 1N. HCl, washed three times with ethyl acetate, the aqueous phase is evaporated to a small volume and stored in the refrigerator overnight. The resulting precipitate was filtered off and dried, yielding isoquinolin-4-yl-acetic acid hydrochloride, MH ⁺ 188.

The intermediate connection 27

To a suspension of ethyl ether (1-chloro-6,7-dimethoxyisoquinolin-4-yl) acetic acid (0.200 g, 0.65 mmol) in toluene (1 ml), an excess of morpholine was added and the mixture was refluxed until the starting material was completely consumed. . After evaporation, the residue was partitioned between water and dichloromethane, the organic phase was dried over magnesium sulfate and evaporated to give ethyl (6,7-dimethoxy-1-morpholin-4-yl-isoquinolin-4-yl) acetic acid [MH] ⁺ 361. The crude ether (0.240 g, 0.66 mmol) was dissolved in ethanol (20 ml), treated with 2 M sodium hydroxide (3 ml) and stirred at room temperature overnight. Then conc. hydrochloric acid to pH 1, the solvent is evaporated, the crude acid is used to obtain a xanthine derivative.

The intermediate connection 28

[6,7-Dimethoxy-1- (4-methylpiperazin-1-yl) isoquinolin-4-yl] acetic acid ethyl ester (0.186 g, 38%) was prepared according to the procedure described for the preparation of intermediate 27, using morpholine instead excess N-methylpiperazine. ¹ H NMR (DMSO-d6): δ 1.19 (t, J7 3H), 2.30 (s, 3H), 2.61 (m, 4H), 3.10-3.30 (m, 4H) 3.92 (s, 6H), 3.97 (s, 2H), 4.10 (q, J7 2H), 7.19 (s, 1H), 7.37 (s, 1H), 7.91 (s, 1H). The crude ether (0.186 g, 0.50 mmol) was dissolved in ethanol (20 ml), treated with 2 M sodium hydroxide (3 ml) and stirred at room temperature overnight. Then conc. hydrochloric acid to pH 1, the solvent is evaporated, the crude acid is used to obtain a xanthine derivative.

The intermediate connection 29

To a solution of 6-methoxyisoquinoline (Synth. Commun., 29, 1617 (1999)) (0.207 g, 1.30 mmol) in acetic acid (9 ml) was added N-chlorosuccinimide (0.347 g, 2.60 mmol) and the reaction mixture heated at 50 ° C for 3 hours. Then the mixture was cooled to room temperature, evaporated and partitioned between ethyl acetate and 1 M sodium hydroxide. The organic phase is washed with water, brine, dried over magnesium sulfate and evaporated to give 5-chloro-6-methoxyisoquinoline, [MH] ⁺ 194. A solution of the obtained intermediate compound (0.175 g, 0.90 mmol) in THF (4, 5 ml) and acetic anhydride (0.101 ml, 1.08 mmol) are treated with sodium triacetoxyborohydride (0.229 g, 1.08 mmol) and the reaction mixture is stirred at room temperature for 22 hours. Then the solvent is evaporated, the residue is taken up in ethyl acetate, washed with 0. 5 M hydrochloric acid, saline and dried over magnesium sulfate. After evaporation, 1- (5-chloro-6-methoxy-1H-isoquinolin-2-yl) ethanone is obtained, _m.p. 78-80 ° C. A suspension of the resulting intermediate (0.150 g, 0.60 mmol) and glyoxylic acid (76 mg, 0.80 mmol) in 6 M hydrochloric acid (2.8 ml) was heated at 100 ° C. for 3 hours. After cooling to room temperature temperature, the resulting solid was separated by filtration to give (5-chloro-6-methoxyisoquinolin-4-yl) acetic acid, [MH] ⁺ 252. A suspension of the obtained intermediate (0.970 g, 3.38 mmol) and ammonium formate (1 , 05 g, 16.9 mmol) in acetic acid / water 1: 1 (25 ml), treated with 10% Pd / C (0.730 g) and stirred at room temperature for 16 hours. the filtered through Celite, the combined filtrate and washings layers were evaporated, the residue was purified by extraction in Soxhlet with acetone to afford (6-methoxyisoquinoline-4-yl) acetic acid, [MH] ⁺ 218. In another embodiment (6-methoxyisoquinoline-4 -yl) acetic acid is obtained by reducing (5-chloro-6-methoxyisoquinolin-4-yl) acetic acid according to the following procedure: a suspension of (5-chloro-6-methoxyisoquinolin-4-yl) acetic acid (20 g, 69.4 mmol ) in a 1 M solution of sodium hydroxide (400 ml) is stirred for 20 minutes, the resulting salt is separated by filtration and about work with hydrogen in the presence of 10% Pd / C (1.4 g) at atmospheric pressure for 2.25 hours. The resulting suspension is filtered through a glass fiber filter and celite, washed with water (50 ml), the solution is cooled in an ice bath and slowly (in within 30 min) is neutralized and then acidified with 5 M hydrochloric acid (80 ml). First, a suspension is formed, and after aging at 5 ° C for 20 hours, crystallization occurs. The resulting crystals were separated by filtration, washed with ethanol (25 ml), cooled in an ice bath, and dried under reduced pressure to give (6-methoxyisoquinolin-4-yl) acetic acid.

The intermediate connection 30

To 1- (6-chloro-1H-isoquinolin-2-yl) ethanone (J. Org. Chem., 45, 1950 (1980)) (1.44 g, 5.90 mmol) in 6N. HCl (24 ml) was added glyoxylic acid (1.37 g, 9.28 mmol) and the reaction mixture was heated at 100 ° C for 3 hours. Then the mixture was cooled to room temperature, washed with ether and evaporated to a volume of 10 ml. After keeping the mixture in the refrigerator overnight, the solid was separated by filtration and dried to give (6-chloroisoquinolin-4-yl) acetic acid hydrochloride. ¹ H NMR (400 MHz, DMSO): δ 4.45 (s, 2H), 8.18 (d, J9 1H), 8.52 (s, 1H), 8.70 (d, J8 1H), 8 83 (s, 1H); 9.96 (s, 1H).

The intermediate connection 31

To a cooled solution (0 ° C) of 6-bromoisoquinoline (J. Chem. Soc. Perkin Trans 2, 437 (1998)) (1.544 g, 7.42 mmol) in acetic acid (10 ml) and acetic anhydride (3 ml) sodium borohydride (1.12 g, 29.6 mol) was added in portions and the resulting mixture was heated at 60 ° C for 4 hours. Then the mixture was cooled, evaporated, diluted with water, made basic with potassium carbonate to pH 10 and extracted with ethyl acetate. The combined organic phases are washed twice with 0.5 N. HCl, brine, dried over sodium sulfate and evaporated to give 1- (6-bromo-1H-isoquinolin-2-yl) ethanone, MH ⁺ 253. K 1- (6-bromo-1H-isoquinolin-2 -yl) ethanone (1.50 g, 5.90 mmol) in 6N. HCl (20 ml) was added glyoxylic acid (0.812 g, 8.80 mmol) and the reaction mixture was heated at 100 ° C for 2 hours. Then the mixture was cooled to room temperature and washed with ethyl acetate. After evaporation, the residue was taken up in methanol (20 ml), conc. Sulfuric acid (10 drops) was added and the mixture was refluxed for 14 hours. The solvent was partially evaporated, the resulting solid was filtered off, washed with methanol and dried to give hydrochloride. methyl ester (6-bromisoquinolin-4-yl) acetic acid, MH ⁺ 281. To a cooled solution (0 ° C) of methyl ester (6-bromisoquinolin-4-yl) acetic acid (50 mg, 0.18 mmol) in THF / water 3: 1 (3 ml) lithium hydroxide hydrate (8.5 mg, 0.20 mmol) was added. After 1 h, the solvent was evaporated, and the lithium salt of (6-bromisoquinolin-4-yl) acetic acid, MH ⁺ 266, was obtained.

The intermediate connection 32

To a suspension of methyl ester (6-bromoisoquinolin-4-yl) acetic acid (0.325 g, 1.03 mmol) in DMF (1.75 ml) and triethylamine (10 ml) was added trimethylsilylacetylene (0.17 ml, 1.23 mmol) ), then copper (I) iodide (40 mg, 0.20 mmol) and (Ph ₃ P) ₂ PdCl ₂ (73 mg, 0.10 mmol) and the reaction mixture is heated at 45 ° C for 40 minutes. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with water, brine, the organic phase was dried over magnesium sulfate, evaporated and the residue was purified by flash column chromatography (eluting with ethyl acetate / hexane, 1: 1) to give methyl ether ( 6-trimethylsilane ethynylisoquinolin-4-yl) acetic acid, [MH] ⁺ 298. The resulting intermediate (0.221 g, 0.74 mmol) was dissolved in methanol (7.5 ml) and treated with potassium carbonate (75 mg, 0.54 mmol) ) The reaction mixture was stirred for 30 minutes at room temperature, evaporated, the residue was purified by flash chromatography (eluting with dichloromethane / methanol, 5: 1) to give (6-ethynylisoquinolin-4-yl) acetic acid, [MH] ⁺ 212 .

The intermediate connection 33

To a chilled (0 ° C) solution of 6-methoxyisoquinoline (Synth. Commun., 29, 1617 (1999)) in dichloromethane (10 ml) was added bromine (0.211 ml, 6.28 mmol) and the reaction mixture was stirred at room temperature for 20 hours. Then the mixture was poured into a 1 M aqueous solution of sodium hydroxide, the organic phase was washed with brine, dried over magnesium sulfate and evaporated. The crude product is purified by flash column chromatography (eluting with dichloromethane / methanol, 20: 1) to give 5-bromo-6-methoxyisoquinoline, [MH] ⁺ 240. Then, (5-bromo-6-methoxyisoquinoline is obtained from the obtained compound) -4-yl) acetic acid, [MH] ⁺ 298, according to the method for preparing intermediate 29.

The intermediate connection 34

[1- (3,5-Diisopropoxyphenyl) -6,7-dimethoxyisoquinolin-4-yl] acetic acid was prepared according to the General Procedure for the Preparation of Intermediate 20, ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.25 (d, J6 12H), 3.78 (s, 3H), 3.86 (s, 2H), 3.92 (s, 3H), 6.46 (d, J 0.5 1H), 6.65 (d, J 0.5 2H), 7.20 (s, 2H), 8.30 (s, 1H).

The following compounds are obtained in the same manner as described in the preparation of intermediate 21.

The intermediate connection 35

1- (3,5-Dimethoxyphenyl) -6-isopropoxy-7-methoxyisoquinolin-4-yl] acetic acid, [MH] ⁺ 412.

The intermediate connection 36

(1-tert-Butyl-6-isopropoxy-7-methoxyisoquinolin-4-yl) acetic acid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.32 (d, J7 6H), 1.52 (s, 9H), 3.80 (s, 2H), 3.90 (s, 3H), 4.75 (heptet, J7 1H), 7.28 (s, 1H), 7.66 (s, 1H), 8 08 (s, 1H).

The intermediate connection 37

(6-Isopropoxy-1-isopropyl-7-methoxyisoquinolin-4-yl) acetic acid, [MH] ⁺ 318.

The following compounds are obtained in the same manner as described in the preparation of intermediate 20:

The intermediate connection 38

(6,7-Dimethoxy-1-methylisoquinolin-4-yl) acetic acid, [MH] ⁺ 262.

The intermediate connection 39

(1-tert-Butyl-6,7-dimethoxyisoquinolin-4-yl) acetic acid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.75 (s, 9H), 3.95 (s, 6H), 4.04 (s, 2H), 7.28 (s, 1H), 7.75 (s, 1H), 8.66 (s, 1H).

Intermediate 40

(1-Isopropyl-6,7-dimethoxyisoquinolin-4-yl) acetic acid, identified as ethyl ether, ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.25 (t, J7 3H), 1.45 ( d, J7 3H), 3.82 (heptet, J7 1H), 3.90 (s, 2H), 3.08 (s, 2H), 4.15 (q, J7 2H), 7.28 (s, 1H), 7.48 (s, 1H), 8.30 (s, 1H).

The intermediate connection 41

2- (7-Methoxy-1-morpholin-4-yl-isoquinolin-4-yl) propionic acid, t _pl. 225-227 ° C., Obtained in the same manner as described in the preparation of intermediate 27.

The following compounds are obtained in the same manner as described in the preparation of intermediate 22

The intermediate connection 42

The lithium salt of (7-hydroxy-6-methoxyisoquinolin-4-yl) -acetic acid, [MH] ⁺ 332, is obtained through (3-benzyloxy-4-methoxybenzyl) - (2,2-dimethoxyethyl) amine.

The intermediate connection 43

(6,7-Dimethoxy-3-methylisoquinolin-4-yl) acetic acid, ¹ H NMR (400 MHz, DMSO): δ 2.50 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 4.02 (s, 2H), 7.30 (s, 1H), 7.43 (s, 1H), 8.30 (s, 1H).

The intermediate connection 44

(6-Ethoxy-7-methoxyisoquinolin-4-yl) acetic acid, 3M ⁺ 261.

The following compounds are prepared as described in the preparation of intermediate 22, using pyruvic acid instead of glyoxylic acid.

The intermediate connection 45

Lithium salt of 2- (6-ethoxy-7-methoxyisoquinolin-4-yl) propionic acid, identified as methyl ester, M ⁺ 290.

The intermediate connection 46

Lithium salt of 2- (7-ethoxy-6-methoxyisoquinolin-4-yl) propionic acid, identified as methyl ester, M ⁺ 290.

The intermediate connection 47

2- (6,7-dimethoxyisoquinolin-4-yl) propionic acid, identified as methyl ester, M ⁺ 267.

The intermediate derivative 48

(8-Fluoro-6-methoxyisoquinolin-4-yl) -acetic acid was obtained in the same manner as described for intermediate derivative 31, and was identified as methyl ester, [MH] ⁺ 250.

The intermediate connection 49

(6,7-Dimethoxyisoquinolin-4-yl) acetic acid and intermediate 50, [1,3] dioxolo [4,5-g] isoquinolin-8-ylacetic acid are prepared as described in Dyke et al., Tetrahedron 24, 1467 (1968).

The intermediate connection 51

(7-Methoxyisoquinolin-4-yl) acetic acid is prepared as described in Dyke et al., Tetrahedron, 29, 3881 (1973).

The intermediate connection 52

To a solution of 3-fluoro-4-methoxybenzaldehyde (20 g, 0.13 mol) in toluene (200 ml) was added 2,2-dimethoxyethylamine (13.85 ml, 0.13 mol), the resulting solution was purged with nitrogen gas and boiled with reflux in a Dean-Stark apparatus overnight. The solvent was then removed under reduced pressure to give (2,2-dimethoxyethyl) - [1- (3-fluoro-4-methoxyphenyl) methylidene] amine. The resulting intermediate (31 g, 0.13 mol) was dissolved in ethyl acetate and acetic anhydride (13.1 g, 0.13 mol) was added. Then, platinum oxide (0.3 g) is added in a stream of nitrogen, and the resulting mixture is stirred in a hydrogen atmosphere until the absorption of hydrogen is complete. The mixture was filtered, washed with saturated aqueous NaHCO ₃ (3 × 100 ml), brine and water, dried over MgSO ₄ and concentrated to give N- (2,2-dimethoxyethyl) -N- (3-fluoro-4- methoxybenzyl) acetamide. The resulting intermediate (38.9 g, approximately 0.13 mol) was dissolved in anhydrous CH ₂ Cl ₂ , and then AlCl ₃ (90 g) and CH ₂ Cl _{2 were} slowly added to the stirred mixture under nitrogen atmosphere. The total volume of CH ₂ Cl ₂ is 250 ml. The mixture was stirred at room temperature for 10 minutes, and then 40% NaOH solution was slowly added while cooling in an ice bath. The mixture was then diluted with water (250 ml), filtered through a glass fiber filter, the organic phase was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 200 ml). The extracts were dried over MgSO ₄ and evaporated under reduced pressure to give a crude oily product, which was purified by flash chromatography on silica gel (eluent: 1% methanol in CH ₂ Cl ₂ ), whereby 1- (7) was obtained as one of the products -fluoro-6-methoxy-1H-isoquinolin-2-yl) ethanone. The resulting intermediate (0.60 g, 2.7 mmol) was mixed with glyoxylic acid (0.325 g, 3.5 mmol) and water (10 ml) and the resulting mixture was stirred at room temperature for 20 minutes. Then add conc. hydrochloric acid (10 ml) and the mixture was refluxed for 1 h. The mixture was concentrated and purified by preparative HPLC to give (7-fluoro-6-methoxyisoquinolin-4-yl) acetic acid, [MH] ⁺ 236.

The following compounds are obtained in the same manner as described in the preparation of intermediate 20.

The intermediate connection 53

(1-Methyl-6-methoxyisoquinolin-4-yl) acetic acid.

The intermediate connection 54

(6-Isopropoxy-1-methylisoquinolin-4-yl) acetic acid.

The intermediate connection 55

(6-Ethoxy-1-methylisoquinolin-4-yl) acetic acid.

The intermediate connection 56

To zinc dicyanide (26 mg, 0.22 mmol) in a nitrogen atmosphere, a solution in DMF (3 ml) of methyl ester (6-bromisoquinolin-4-yl) acetic acid (52 mg, 0.19 mmol), obtained in the same way, is added. as described in the preparation of intermediate 31. 1,1'-bis (diphenylphosphino) ferrocene (15 mg) and tris (dibenzylideneacetone) dipalladium (0) (8 mg) were added to the resulting mixture, and the resulting mixture was stirred at 120 ° C. for 22 h. The solution is cooled, diluted with chloroform (30 ml), washed with water (2 × 20 ml), brine (20 ml), then chloroform (40 ml) is added, dried over MgSO ₄ , filtered and concentrated. The resulting material was purified by flash column chromatography on a silica gel column (eluent: CH ₂ Cl ₂ / methanol, 40: 1, then CH ₂ Cl ₂ / methanol, 50: 1) to give methyl ester (6-cyanoisoquinoline-4- il) acetic acid [MH] ⁺ 227. The intermediate is saponified by treatment with LiOH in THF / water, 3: 1. The resulting mixture was partially evaporated to remove THF, diluted with water to 10 ml and washed with ethyl acetate. Then the aqueous phase is neutralized with 1 M hydrochloric acid (to pH 4-5) and carefully extracted with ethyl acetate. The organic phase is dried over MgSO ₄ , filtered and concentrated to give (6-cyanoisoquinolin-4-yl) acetic acid M ⁺ 212.

The intermediate connection 57

(5-Chloro-6-methoxyisoquinolin-4-yl) acetic acid was prepared as described in the preparation of intermediate 29.

The intermediate connection 58

To a solution of (6-trimethylsilanylethynylinethylisoquinolin-4-yl) methyl ester (0.19 g, 0.64 mmol) obtained as described in the preparation of intermediate 32 in anhydrous methanol (7 ml) was added K ₂ CO ₃ ( 72 mg) and the resulting mixture was stirred for 1 hour. An additional amount of K ₂ CO ₃ (11 mg) was then added and the mixture was stirred for 30 minutes. The mixture was neutralized with glacial acetic acid and concentrated. The resulting material was purified by flash column chromatography on a silica gel column (ethyl acetate / hexane, 1: 1), whereby methyl (6-ethynylisoquinolin-4-yl) acetic acid, M ⁺ 22 was obtained. The obtained intermediate compound (79 mg, 0, 35 mmol) was dissolved in methanol in an inert gas atmosphere and 10% Pd on carbon (79 mg) was added. The resulting suspension is intensively stirred in an atmosphere of hydrogen. After 90 min, the catalyst was separated by filtration and washed with methanol, the filtrate was concentrated, and methyl (6-ethylisoquinolin-4-yl) acetic acid was obtained, M ⁺ 229. To a solution of the obtained intermediate compound (68 mg, 0.30 mmol) in THF (methanol / water (3: 1: 1, 3.5 ml), LiOH (12.5 mg) was added and the mixture was stirred at room temperature for 20 hours. Then, the solution was concentrated under reduced pressure to obtain (6-ethylisoquinoline- 4-yl) lithium acetate, M ⁺ 221.

The intermediate connection 59

Intermediate 29 (0.5 g, 2.3 mmol) was suspended in a 48% aqueous HBr solution (10 ml) and heated at 100 ° C. for 48 hours. An additional 48% aqueous HBr solution (10 ml) was then added and heating was continued at 100 ° C. for another 24 hours. The reaction mixture was cooled to 5 ° C. for 4 hours, the resulting solid was filtered off, washed with water and dried under high vacuum at 50 ° C. to give hydrobromide (6-hydroxyisoquinoline -4-yl) acetic acid, [MH] ⁺ 204.4. The resulting intermediate (0.15 g, 0.53 mmol) was suspended in DMF (2 ml), K ₂ CO ₃ (0.22 g, 1.58 mmol) was added to the resulting suspension, then ethyl iodide (0.085 ml, 1 , 06 mmol) and the resulting mixture was stirred at room temperature for 2 h, after which the mixture was concentrated and purified by flash chromatography on a silica gel column (eluent: CH ₂ Cl ₂ / methanol, 10: 1), whereby ethyl ether was obtained ( 6 etoksiizohinolin-4-yl) -acetic acid [MH] ⁺ 260. The resulting intermediate (25 mg, 0.11 mmol) was dissolved in water (1 mL) was added LiOH (5 mg, 0.11 mol) and stirred at room temperature for 30 min. Then acidified with a minimum amount of 6n. HCl and concentrated to give crude (6-ethoxyisoquinolin-4-yl) acetic acid.

Examples 1-70

Compounds of formula I, which may also have the formula

where R ₁ -R ₄ and R ₈ -R ₁₃ have the meanings indicated above, in free or salt form, and methods for their preparation are presented in the table below, and the methods are described below. R ₃ means H in all examples except No. 44, where R ₃ means CH ₃ . R ₄ means H in all examples except No. 25-27 and No. 41-43, where R ₄ means CH ₃ . R ₉ means H in all examples except No. 29, where R ₉ means CH ₃ . R ₁₀ means H in all examples except No. 57, where R ₁₀ means Br, and No. 75, where R ₁₀ means Cl. R ₁₃ means H in all examples except No. 56, where R ₁₃ means F, and No. 65 and 66, where R ₁₃ means Br.

Method A

1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.21 g, 1.30 mmol) was added to 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.223 g, 1.05 mmol) and (6,7-dimethoxy-1-methylisoquinolin-4-yl) acetic acid (0.25 g, 0.96 mmol) in methanol (5 ml) and water (1 ml) and the mixture was stirred at room temperature for 16 hours. Methanol was evaporated, the resulting solid was filtered off, transferred to methanol (5 ml) and 5 M aqueous sodium hydroxide solution (0.5 ml) was added. The reaction mixture was refluxed for 1 h, cooled to room temperature and evaporated. The residue was dissolved in water and extracted with dichloromethane, the combined organic extracts were dried over sodium sulfate and evaporated to give 8- (6,7-dimethoxy-1-methylisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7 -dihydropurin-2,6-dione, M ⁺ 437.

Method B1

(6-Ethynylisoquinolin-4-yl) acetic acid (58 mg, 0.28 mmol) was dissolved in DMF (1 ml) and O- (7-azabenzotriazo-1-yl) -N, N, N ', N hexafluorophosphate was added. '-tetramethyluronium (0.125 g, 0.33 mmol) and Hanig base (0.180 ml, 1.03 mmol), and then a solution of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4 dione (58 mg, 0.28 mmol) in DMF (0.7 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, the residue was purified by flash column chromatography (eluting with dichloromethane / methanol, 30: 1). The resulting intermediate was dissolved in methanol (2 ml), water (2.75 ml) was added, and then 4 M aqueous sodium hydroxide solution (0.25 ml) was added. The reaction mixture is heated at 40 ° C. for 2 hours and then stirred at room temperature for 16 hours. The solvent is evaporated, the crude product is purified by flash column chromatography (eluting with dichloromethane / methanol, 30: 1), whereby 8 - (6-ethynylisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7-dihydropurin-2,6-dione, [MH] ⁺ 388.

Method B2

A suspension of (6-methoxyisoquinolin-4-yl) acetic acid (3.5 g, 13.82 mmol) in acetonitrile (70 ml) was sequentially treated with Hanig base (6.15 ml, 36 mmol), O- (7-benzotriazo hexafluorophosphate) -1-yl) -N, N, N ', N'-tetramethyluronium (6.29 g, 16.6 mmol) and 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidin-2,4 -dione (3.22 g, 15.2 mmol) while stirring the solution at room temperature. Then the reaction mixture was stirred at room temperature for 2 hours, after which the solvent was evaporated. The residue was triturated with ethyl acetate (50 ml), separated by filtration, washed with ethyl acetate and dried at 50 ° C under reduced pressure. The resulting intermediate compound is suspended in a mixture of methanol (30 ml) and 4 M aqueous sodium hydroxide solution (60 ml) and heated at 80 ° C for 45 minutes. The suspension is neutralized with acetic acid and cooled to 0-5 ° C. overnight. The resulting solid was separated by filtration, washed with methanol / water, 1: 9 (30 ml), and then with methanol (30 ml). The resulting material was dried under high vacuum at 50 ° C. to give 3-isobutyl-8- (6-methoxyisoquinolin-4-ylmethyl) -1-methyl-3,7-dihydropurin-2,6-dione, [MH] ⁺ 394.5.

Method B

1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.6 M solution in water, 0.33 ml, 1.85 mmol) is added to a suspension of 5,6-diamino-1-isobutyl-3-methyl-1H- pyrimidin-2,4-dione (0.327 g, 1.54 mmol), (1-chloro-6,7-dimethoxyisoquinolin-4-yl) acetic acid (0.414 g, 1.54 mmol) and 1-hydroxybenzotriazole (0.251 g , 1.85 mmol) in CH ₂ Cl ₂ (2 ml). Water (2 ml) was then added, the resulting biphasic mixture was shaken for 18 hours, and the resulting solid was separated by filtration. The intermediate was suspended in methanol (10 ml), a 4 M aqueous NaOH solution (5 ml) was added and the mixture was refluxed for 4 hours. Methanol was evaporated, the residue was acidified with conc. hydrochloric acid to pH 2, the resulting solid was separated by filtration and purified by preparative HPLC to give 8- (1-chloro-6,7-dimethoxyisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7- hydrochloride dihydropurin-2,6-dione, [MH] ⁺ 458.

Method D

1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide (..., 20.6 ml, 0.11 mol) is added to the mixture of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidin-2,4 dione (20 g, 0.094 mol), (5,6-dimethoxyisoquinolin-4-yl) acetic acid (26.7 g, 0.094 mol) and 1-hydroxybenzotriazole (19.2 g, 0.142 mol) in dichloromethane / water, 1: 1 (400 ml). The reaction mixture was stirred at room temperature for 4.5 hours, the resulting solid was separated by filtration, suspended in water (500 ml), separated by filtration, washed with water (250 ml), dried, triturated with methanol and dried again, whereby an intermediate was obtained the compound is mixed with a less pure product obtained by concentrating the solution in methanol. The intermediate (16.08 g) was dissolved in water (100 ml) and methanol (100 ml), 4 M aqueous sodium hydroxide solution (56 ml) was added and the resulting solution was heated at 70 ° C. overnight. After cooling to room temperature, methanol was evaporated, the residue was acidified with conc. hydrochloric acid to pH 1, the resulting hydrochloride is separated by filtration and dried. The product is then treated with an aqueous solution of sodium hydroxide with a pH of 11 and washed with water to give a free base, 3-isobutyl-8- (5,6-dimethoxyisoquinolin-4-ylmethyl) -1-methyl-3,7-dihydropurin-2, 6-dione [MH] ⁺ 424.6.

Method D

A suspension of the product (72 mg, 0.13 mmol), obtained as described in example 11, in 6N. HCl (2.5 ml) and ethanol (1.5 ml) were refluxed for 5 hours and then allowed to stand at room temperature overnight. The resulting precipitate was separated by filtration, washed with water and dried to give 3- (3-aminobenzyl) -8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -1-methyl-3,7-dihydropurin-2,6- dihydrochloride dione, ¹ H NMR (400 MHz, DMSO): δ 3.20 (s, 3H), 3.95 (s, 3H), 4.00 (s, 3H), 4.75 (s, 2H), 5 15 (s, 2H), 7.15 (m, 2H), 7.20 (s, 1H), 7.30 (t, J6 1H), 7.65 (s, 1H), 7.95 (s , 1H), 8.50 (s, 1H), 9.50 (s, 1H), 13.6 (br s, 1H).

Method E

The product (37 mg, 0.07 mmol) obtained as described in Example 58 was suspended in pyridine (1.5 ml) and dimethyl sulfamoyl chloride (23 ml, 0.21 mmol) was added. The reaction mixture was heated at 50 ° C for 22 hours, after which the solvent was evaporated. After trituration with water, a solid is obtained which is separated by filtration and dried, whereby 3- [3- (N, N-dimethylsulfamoyl) aminobenzyl] -8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -1-methyl- 3,7-dihydropurin-2,6-dione, ¹ H NMR (400 MHz, DMSO): δ 2.64 (s, 6H), 3.26 (s, 3H), 3.86 (s, 3H), 3.98 (s, 3H), 4.50 (s, 2H), 5.15 (s, 2H), 6.98 (d, J6 1H), 7.08 (d, J6 1H), 7.15 (s, 1H), 7.22 (t, J6 3H), 7.55 (s, 1H), 7.62 (s, 1H), 8.38 (s, 1H), 9.15 (s, 1H ), 9.82 (s, 1H), 13.60 (s, 1H).

Method W

The product (100 mg, 0.25 mmol) obtained as described in Example 24 is heated at 100 ° C. in conc. hydrobromic acid (5 ml) for 36 hours, after which the solvent is evaporated and the crude product is purified by preparative HPLC to give 8- (7-hydroxyisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7- dihydropurin-2,6-dione, [M] ⁺ 379.

Method Z

The product (41 mg, 0.09 mmol) obtained as described in Example 64 was dissolved in acetic acid (2 ml) and treated with bromine in acetic acid (solution 148 mg / ml, 100 μl). After keeping at room temperature for 1 h, the solvent was evaporated, the residue was dissolved in hot methanol, filtered and the solvent was evaporated, to give 8- (8-bromo-6,7-dihydroxyisoquinolin-4-ylmethyl) -3-isobutyl-1- methyl-3,7-dihydropurin-2,6-dione, M ⁺ 474,

Method And

A suspension of the product obtained as described in example 13, namely 3-allyl-8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -1-methyl-3,7-dihydropurin-2,6-dione hydrochloride (0.760 g , 1.87 mmol), 9-borabicyclo [2.2.0] nonane (0.5 M solution in THF, 18.7 ml, 9.35 mmol) and diisopropylethylamine (0.33 ml, 1.89 mmol) in THF (9 ml) was refluxed for 2.5 hours. Sodium hydroxide (4 M aqueous solution, 6 ml) and hydrogen peroxide (27.5%, 3 ml) were then added sequentially, and the reaction mixture was heated at 50 ° C. within 1.5 hours. The reaction mixture is evaporated, the crude product is purified express ss chromatography (eluting with CH ₂ Cl ₂ / methanol, 19: 1) and triturated with water to give 8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -3- (3-hydroxypropyl) -1-methyl -3,7-dihydropurin-2,6-dione, [MH] ⁺ 426.

Method K

To a solution of 8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7-dihydropurin-2,6-dione (0.100 g, 0.24 mmol) in DMF (2 ml) obtained as described in Example 10, potassium carbonate (48 mg, 0.35 mmol) and iodomethane (0.018 ml, 0.295 mmol) are added. The reaction mixture was stirred overnight and purified by preparative HPLC to give 8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -3-isobutyl-1,7-dimethyl-3,7-dihydropurin-2,6-dione, [MH] ⁺ 438.

Method L

Suspension of 8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -3- (3-hydroxy-2-methylpropyl) -1-methyl-3,7-dihydropurin-2,6-dione (63 mg, 0.14 mmol ) obtained as described in Example 68 and acetyl chloride (18 ml, 0.25 mmol) in pyridine (1 ml) was heated at 50 ° C for 18 hours. The mixture was evaporated and purified by flash chromatography (eluting with dichloromethane / methanol , 19: 1), whereby 3- [8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] is obtained] Acetic acid -2-methylpropyl ester, [MH] ⁺ 482.

Method M

8- (6,7-Dimethoxyisoquinolin-4-ylmethyl) -1-methyl-3- (2-methylallyl) -3,7-dihydropurin-2,6-dione (100 mg, 0.24 mmol), obtained as described in example 18, suspended in 1,2-dichloroethane (30 ml), diethylzinc (1 M solution in hexane, 1.2 ml, 1.20 mmol) was added, then chlorodiomethane (0.174 ml, 0.24 mmol) and the reaction the mixture was stirred at room temperature for 1 h. The reaction was stopped by the addition of a saturated aqueous solution of NH ₄ Cl. After extraction with chloroform, the organic phase is washed with water, dried over MgSO ₄ and evaporated. The resulting material was purified by preparative HPLC to give 8- (6,7-dimethoxyisoquinolin-4-ylmethyl) -1-methyl-3- (1-methylcyclopropylmethyl) -3,9-dihydropurin-2,6-dione, [MH] ⁺ 436.

Method H

8- (6-Bromisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7-dihydropurin-2,6-dione (245 mg, 0.554 mmol), obtained as described in Example 53, is dispersed in a mixture triethylamine (0.085 ml, 0.61 mmol) and CH ₂ Cl ₂ (4 ml). A solution of di-tert-butoxycarbonate (133 mg, 0.61 mmol) in CH ₂ Cl ₂ (1 ml) was added dropwise to the stirred mixture, after 2 h, triethylamine (0.170 ml, 1.2 mmol), di-tert- butoxycarbonate (130 mg, 0.60 mmol), DMF (0.3 ml) and stirred at room temperature for 2.5 days. The reaction mixture was then concentrated, partitioned between water and hexane, sonicated, filtered, re-concentrated and purified by flash column chromatography on a silica gel column (eluting with CH ₂ Cl ₂ / methanol, 19: 1) to give tert-butyl ether 8 - (6-bromoisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-carboxylic acid ([MH] ⁺ 543). The intermediate (58 mg, 0.11 mmol) is added to Zn (CN) ₂ (15 mg, 0.13 mmol), then 1,1'-bis (diphenylphosphino) ferrocene (9 mg), tris (dibenzylideneacetone) dipalladium are added. (0) (5 mg) and anhydrous DMF (2.5 ml) and the resulting mixture was stirred at 120 ° C. for 18 hours and then at 150 ° C. for another 24 hours. Zn (CN) ₂ (57) was then added. mg, 0.49 mmol), anhydrous DMF (1 ml) and the mixture is heated at 155 ° C for 2 hours and then at 145 ° C for 18 hours. Then 1,1'-bis (diphenylphosphino) ferrocene ( 9 mg), Tris (dibenzylideneacetone) dipalladium (0) (9 mg) and the reaction mixture is heated at 145 ° C for ue additional 6 hours The mixture was concentrated, triturated with water, filtered, washed with a saturated NaHCO ₃ / water, 1: 1., then extracted with CH ₂ Cl ₂ and MeOH / CH ₂ Cl _2, 1: 1 and purified by repeated flash chromatography on a silica gel column (eluting with CH ₂ Cl ₂ / methanol, 10: 1 and CH ₂ Cl ₂ / methanol, 20: 1) to give 4- (3-isobutyl-1-methyl-2,6-dioxo- 2,3,6,7-tetrahydro-1H-purin-8-ylmethyl) isoquinoline-6-carbonitrile, [MH] ⁺ 389.

Method O

To 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidin-2,4-dione (0.40 g, 1.9 mmol) and (1-chloro-6,7-dimethoxyisoquinolin-4-yl ) acetic acid (0.39 g, 1.78 mmol) in methanol and water add 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.29 g, 1.9 mmol) and the mixture is stirred at room temperature for 2 hours. Methanol was evaporated, the resulting solid was filtered off and recrystallized from ethyl acetate / methanol. The solid is then heated in a sealed ampoule (100 ° C, 8 hours) with a 40% aqueous solution of dimethylamine. The mixture was evaporated and extracted with ethyl acetate. The ethyl acetate solution was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (eluting with ethyl acetate / methanol) to give 8- (1-dimethylamino-6,7-dimethoxyisoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7 -dihydropurin-2,6-dione, MH ⁺ 467.

Method P

To 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidin-2,4-dione (0.40 g, 1.9 mmol) and (1-chloro-6,7-dimethoxyisoquinolin-4-yl ) acetic acid (0.39 g, 1.78 mmol) in methanol and water add 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.29 g, 1.9 mmol) and the mixture is stirred at room temperature for 2 hours. Methanol was evaporated, the resulting solid was filtered off and recrystallized from ethyl acetate / methanol. A mixture of the resulting solid with piperidine was refluxed for 8 hours. The solution was filtered, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (eluting with ethyl acetate / methanol) to give a solid which is dissolved in 1N. NaOH (20%) / methanol and refluxed for 2 hours. The mixture was concentrated, water was added, it was extracted with ethyl acetate, the organic phase was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 8- (6,7-dimethoxy-1-piperidin-1-yl-isoquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7-dihydropurin-2,6-dione, MH ⁺ 507.

The parameters of the proton NMR spectra of the compounds obtained in examples No. 12-23 and No. 49, ( ¹ H 400 MHz, DMSO-d6)

Example 12

δ 3.25 (s, 3H), 3.92 (s, 3H), 4.02 (s, 3H), 4.65 (s, 2H), 7.70 (s, 1H), 7.88 ( s, 1H), 8.45 (s, 1H), 9.42 (s, 1H), 11.1 (s, 1H), 13.60 (s, 1H)

Example 13

δ 3.20 (s 3H), 4.95 (s 3H), 4.00 (s 3H), 4.52 (d J4 2H), 4.70 (s 2H), 5.04 (d J18 1H) 5.09 (d J10 1H), 5.88 (m 1H), 7.60 (s 1H), 7.88 (s 1H), 8.46 (s 1H), 9.42 (s 1H), 13.7 (s 1H).

Example 14

δ 0.20-0.40 (m, 4H), 1.10-1.30 (m, 1H), 3.21 (s, 3H), 3.81 (m, 2H), 3.98 (s , 3H), 4.03 (s, 3H), 4.66 (s, 2H), 7.65 (s, 1H), 7.85 (s, 1H), 8.45 (s, 1H), 9 39 (s, 1H); 13.70 (s, 1H).

Example 15

δ 0.82 (s, 9H), 3.20 (s, 3H), 3.78 (s, 2H), 3.99 (s, 3H), 4.04 (s, 3H), 7.62 ( s, 1H), 7.90 (s, 1H), 8.45 (s, 1H), 9.44 (s, 1H), 13.60 (s, 1H).

Example 16

δ 0.81 (d, J7 12H), 1.98 (m, 1H), 2.12 (m, 1H), 3.70 (d, J8 2H), 3.78 (d, J7 2H), 3 99 (s, 3H), 4.05 (s, 3H), 4.70 (s, 2H), 7.65 (s, 1H), 7.90 (s, 1H), 8.46 (s, 1H), 9.45 (s, 1H), 13.6 (s, 1H).

Example 17

δ 0.80-1.10 (m, 6H), 1.40-1.60 (m, 4H), 1.80 (m, 1H), 3.15 (s, 1H), 3.76 (d , J8 2H), 3.91 (s, 3H), 4.02 (s, 3H), 4.68 (s, 2H), 7.60 (s, 1H), 7.88 (s, 1H), 8, 44 (s, 1H); 13.60 (s, 1H).

Example 18

δ 1.69 (s, 3H), 3.21 (s, 3H), 3.98 (s, 3H), 4.01 (s, 3H), 4.46 (s, 2H), 4.52 ( s, 1H), 4.68 (s, 2H), 4.76 (s, 1H), 7.58 (s, 1H), 7.84 (s, 1H), 8.45 (s, 1H), 9.42 (s, 1H); 13.60 (s, 1H).

Example 19

δ 1.50-1.85 (m, 4H), 3.18 (s, 3H), 3.50-3.85 (m, 4H), 3.95 (s, 3H), 4.02 (s , 3H), 4.10-4.20 (m, 1H), 4.70 (s, 2H), 7.75 (s, 1H), 7.920 (s, 1H), 8.50 (s, 1H) 9.50 (s, 1H); 13.60 (broad s, 1H).

Example 20

δ 0.70-0.80 (m, 6H), 0.99-1.10 (m, 1H), 1.20-1.25 (m, 1H), 1.88-2.00 (m, 1H), 3.21 (s, 3H), 3.64-3.80 (m, 2H), 3.95 (s, 3H), 4.00 (s, 3H), 4.68 (s, 2H ), 7.60 (s, 1H), 7.80 (s, 1H), 8.45 (s, 1H), 9.42 (s, 1H), 13.60 (broad s, 1H).

Example 21

δ 0.83 (t, J8 3H), 1.63 (sextet, J8 2H), 3.83 (t, J8 2H), 3.99 (s, 3H), 4.05 (s, 3H), 4 69 (s, 2H), 7.64 (s, 1H), 7.88 (s, 1H), 8.44 (s, 1H), 9.42 (s, 1H), 11.10 (s, 1H) 13.60 (s, 1H).

Example 23

δ 0.80 (d, J7 6H), 3.18 (s, 3H), 3.75 (d, J8 2H), 4.60 (s, 2H), 6.32 (s, 2H), 7, 71 (s, 1H), 7.82 (s, 1H), 8.50 (s, 1H), 9.42 (s, 1H), 13.50 (s, 1H).

Example 49

δ 0.12-0.25 (m, 4H), 1.02-1.10 (m, 1H), 3.20 (s, 3H), 3.68 (d, J7 2H), 4.00 ( s, 3H), 4.80 (s, 2H), 7.70 (d, J9 1H), 8.21 (d, J9 1H), 8.38 (s, 1H), 9.20 (s, 1H ), 13.10 (s, 1H).

Example 86

3-Isobutyl-1-methyl-8- [1- (6-methyl-5-oxo-5,6-dihydro [1,3] dioxolo [4,5-.g.] Isoquinolin-8-yl) ethyl ] -3,7-dihydropurin-2,6-dione

Benzo [1,3] dioxol-5-ylmethyl- (2,2-dimethoxyethyl) amine (see Tetrahedron, 24, 1467 (1968)) is treated with pyruvic acid according to the general procedure for the preparation of intermediate 22, whereby 2- [ 1,3] dioxolo [4,5-.g.] Isoquinolin-8-ylpropionic acid, t _pl. 224-226 ° C. After treating the resulting compound with gaseous HCl in ethanol, the corresponding ethyl ether hydrochloride is obtained, _mp. 223-225 ° C. A solution of the indicated compound (2.73 g, 10 mmol) in benzene (20 ml) was treated with dimethyl sulfate (1.26 g, 10 mmol) and stirred at room temperature for 5 hours, after which the solvent was evaporated. The crude oily product is dissolved in water (20 ml), cooled to 0-5 ° C and a solution of K ₃ Fe (CN) ₆ (5.72 g, 17.4 mmol) in water (25 ml) and sodium hydroxide (2 , 04 g, 51 mmol) in water (15 ml). After keeping the reaction mixture at 5 ° C. for 1.5 hours, the reaction mixture was acidified with conc. Hydrochloric acid to pH 2 and the product was separated by filtration and then crystallized from methanol / dichloromethane to give 2- (6-methyl-5-oxo -5,6-dihydro- [1,3] dioxolo [4,5-.g.] Isoquinolin-8-yl) propionic acid, t _pl. 290 ° C (decomp.). Xanthine is prepared from the intermediate by the general procedure described in Example D, [MH] ⁺ 452.

Example 87

8- (6,7-Dimethoxyquinolin-4-ylmethyl) -3-isobutyl-1-methyl-3,7-dihydropurin-2,6-dione

Lithium diisopropylamide (2M solution in pentane, 2.46 ml, 4.92 mmol) and potassium tert-butoxide (0.552 g, 4.92 mmol) are added to THF (10 ml) at -70 ° C, and then 6, 7-dimethoxy-4-methylquinoline (J. Org. Chem., 623, 568 (1997)) (1.0 g, 4.92 mmol). After 1 h, the reaction mixture was poured into excess crushed dry ice and warmed to room temperature overnight. Pyridine hydrochloride (0.57 g, 4.92 mmol) is then added and the reaction mixture is partitioned between ether and water. The aqueous phase is evaporated, the residue is taken up in hot methanol, treated with charcoal, filtered through celite and evaporated to give (6,7-dimethoxyquinolin-4-yl) acetic acid, MH ⁺ 248. Xanthine is obtained from the intermediate according to the general procedure described in example B, t _pl. > 250 ° C.

Claims (6)

1. The compound of the formula

in free form or in salt form, where R ¹ means hydrogen or C ₁ -C ₄ alkyl, R ² means C ₁ -C ₈ alkyl, hydroxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkylcarbonyloxyC ₁ -C ₈ alkyl, C ₂ -C ₄ alkenyl, C ₃ -C ₆ cycloalkyl C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylC ₃ -C ₆ cycloalkylC ₁ -C ₄ alkyl, tetrahydrofuranyl C ₁ -C ₄ alkyl, phenylC ₁ -C ₄ alkyl, in which phenyl is optionally substituted with one or more substituents selected from the series C ₁ -C ₄ alkoxy, amino , C ₁ -C ₄ alkylcarbonylamino, halogen, C ₁ -C ₄ alkylsulfonylamino or di (C ₁ -C ₄ alkyl) aminosulfonylamino, or optionally fused to a 5-membered heterocycle containing two oxygen atoms in the ring, R ³ means hydrogen or C ₁ -C ₄ alkyl, R ⁴ means hydrogen or C ₁ -C ₄ alkyl, R ⁵ means an isoquinolinyl group of formula III

where R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently of one another means hydrogen or a substituent selected from the range of halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy , C ₂ -C ₄ alkynyl, carboxyl, C ₁ -C ₄ alkylamino, C ₁ -C ₄ alkoxyphenyl, morpholinyl, C ₁ -C ₄ alkylpiperazinyl and piperidinyl, or R ¹¹ and R ¹² together with the carbon atoms to which they are attached , mean a 5-membered heterocyclic group containing two oxygen atoms in the ring. 2. The compound according to claim 1, in which (I) R ¹ means CH ₃ , R ² means (CH ₃ ) ₂ CHCH ₂ , R ³ and R ⁴ each means H, R ⁸ means CH ₃ , R ⁹ and R ¹⁰ each means H, and R ¹¹ and R ¹² each means OCH ₃ ; or (II) R ¹ means CH ₃ , R ² means (CH ₃ ) ₂ CHCH ₂ , R ³ , R ⁴ , R ⁸ , R ⁹ and R ¹⁰ each means H, and R ¹¹ and R ¹² each means OCH ₃ ; or (III) R ¹ means CH ₃ , R ² means (CH ₃ ) ₃ CCH ₂ , R ³ , R ⁴ , R ⁸ , R ⁹ and R ¹⁰ each means H, and R ¹¹ and R ¹² each means OCH ₃ ; or (IV) R ¹ means CH ₃ , R ² means (CH ₃ ) ₂ CHCH ₂ , R ³ , R ⁴ , R ⁹ and R ¹⁰ each means H, R ⁸ means Cl, and R ¹¹ and R ¹² each means OCH ₃ ; or (V) R ¹ means CH ₃ , R ² means (CH ₃ ) ₂ CHCH ₂ , R ³ , R ⁴ , R ⁸ , R ⁹ and R ¹⁰ each means H, R ¹¹ means OCH ₃ , and R ¹² means H; or (VI) R ¹ is CH ₃ , R ² is cyclopropylmethyl, R ³ , R ⁴ , R ⁸ , R ⁹ , R ¹⁰ and R ^{11 are} each H, and R ¹¹ is OCH ₃ ; or (VII) R ¹ is CH ₃ , R ² is (CH ₃ ) ₂ CHCH ₂ , R ³ , R ⁴ , R ⁸ , R ⁹ , R ¹⁰ and R ^{12 are} each H, and R ¹¹ is CH≡C or (VIII) R ¹ is CH ₃ , R ² is 4- (N-dimethylaminosulfonylamino) benzyl, R ³ , R ⁴ , R ⁸ , R ⁹ and R ^{10 are} each H, and R ¹¹ and R ^{12 are} each OCH ₃ ; or (IX) R ¹ means CH ₃ , R ² means HOC ₂ CH (CH ₃ ) CH ₂ , R ³ , R ⁴ , R ⁸ , R ⁹ and R ¹⁰ each means H, and R ¹¹ and R ¹² each means OCH ₃ ; or (X) R ¹ is CH ₃ , R ² is 1-methylcyclopropylmethyl, R ³ , R ⁴ , R ⁸ , R ⁹ and R ^{10 are} each H, and R ¹¹ and R ^{12 are} each OCH ₃ . 3. A pharmaceutical composition for treating a condition mediated by PDES, comprising, as an active ingredient, a compound according to claim 1 or 2, optionally in admixture with a pharmaceutically acceptable diluent or carrier. 4. A pharmaceutical composition for treating erectile dysfunction, comprising, as an active ingredient, a compound according to claim 1 or 2, optionally in admixture with a pharmaceutically acceptable diluent or carrier. 5. A pharmaceutical composition for treating pulmonary hypertension, comprising, as an active ingredient, a compound according to claim 1 or 2, optionally in admixture with a pharmaceutically acceptable diluent or carrier. 6. A process for preparing a compound of formula I in free or salt form, which comprises dehydrating a compound of formula

where R ¹ , R ² , R ⁴ and R ⁵ have the meanings indicated in claim 1, and the selection of the obtained product of formula I in free form or in salt form.